Copper complexes for the treatment of neurodegenerative disorders

Abstract

The present disclosure relates to copper complexes, pharmaceutical compositions containing these complexes, chemical processes for preparing these complexes, and their use in the treatment of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS).

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Ser. No. 63 / 070,792, filed August 26, 2020, the disclosure of which is incorporated herein by reference in its entirety. [Background technology]

[0002] Neurodegenerative diseases are age-dependent disorders that are becoming increasingly prevalent, due in part to the growing elderly population (Heemels, Nature (2016) 539:179).

[0003] For example, amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, Lou Gehrig's disease, or Charcot's disease, is estimated to affect 30,000 Americans and over 400,000 people worldwide at any given time. Approximately 5,000 Americans are diagnosed with ALS each year. The disease causes the relentless death of motor neurons, resulting in progressive paralysis that, on average, kills its victims within one to five years. Most people diagnosed with ALS survive three to five years after the first signs of the disease. Approximately 10% of people with ALS survive at least 10 years. The variable rate of disease progression makes prognosis difficult to predict and the development of therapies challenging.

[0004] Only two drugs (riluzole and edaravone) are approved by the FDA for the treatment of ALS, and both can slow disease progression and extend lifespan by up to several months in a subset of patients, but neither can treat or cure the disease.

[0005] Some inherited forms of ALS are caused by genetic mutations that alter an enzyme in cells called copper-zinc superoxide dismutase (Cu-Zn superoxide dismutase, now commonly called SOD1), which functions to keep cells safe from metabolic waste products that can cause damage if not neutralized.

[0006] The compound CuATSM has been shown to be protective in a transgenic mouse model of ALS in which transgenic mice were engineered to express human SOD1 with the mutation found in SOD1 familial ALS, using rigorous methods established in the art.

[0007] However, there is a need in the art for improved therapeutic agents that can treat neurological diseases and / or copper deficiency-related disorders. Summary of the Invention

[0008] Provided herein are compounds useful in methods for treating or preventing neurodegenerative diseases in a subject in need thereof.

[0009] In one aspect, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein L, R1, R2, R3, and R4 are as defined herein.

[0010] In certain embodiments, the compound of formula (I) is selected from the group consisting of compounds 1-22, or a pharmaceutically acceptable salt thereof.

[0011] In another aspect, the present disclosure provides a compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and R4 are as defined herein.

[0012] In one embodiment, the compound of formula (II) is selected from the group consisting of compounds 23-46.

[0013] In another aspect, the present disclosure provides a compound of formula (III): [ka] or a pharmaceutically acceptable salt thereof, wherein L, R1, R2, and R3 are as defined herein.

[0014] In one embodiment, the compound of formula (III) is selected from the group consisting of compounds 47-53.

[0015] In another aspect, the present disclosure provides a compound of formula (IV): [ka] or a pharmaceutically acceptable salt thereof, wherein L, R1, R2, R3, and R4 are as defined herein.

[0016] In certain embodiments, the compound of formula (IV) is selected from the group consisting of compounds 1-22, 57, 59-61, and 66-78.

[0017] In another aspect, the present disclosure provides a compound of formula (V): [ka] or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and R4 are as defined herein.

[0018] In certain embodiments, the compound of formula (V) is selected from the group consisting of compounds 23-46 and 79-127.

[0019] In another aspect, the disclosure provides a compound selected from the group consisting of compounds 56-65.

[0020] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0021] In another aspect, the disclosure provides a method of treating or preventing a neurodegenerative disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure.

[0022] In one embodiment, the neurodegenerative disease is amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Parkinson's disease, Huntington's disease, and Alzheimer's disease. In another embodiment, the neurodegenerative disease is ALS. In a further embodiment, the ALS is familial or sporadic.

[0023] In another aspect, the disclosure provides methods of making the compounds of the disclosure. [Brief explanation of the drawings]

[0024] [Figure 1] (A) illustrates the change from baseline in compound muscle action potential (CMAP) in male SOD1G93A mice after 4 weeks of daily treatment with 10 mg / kg or 30 mg / kg CuATSM or vehicle. (B) Percent of baseline for the same cohort after CuATSM or vehicle dosing. [Figure 2] Figure A illustrates the change from baseline in CMAP after 5 weeks of daily administration of 10 mg / kg or 30 mg / kg of Compound 25 or vehicle (control) to male SOD1G93A mice. Figure B illustrates the percentage of baseline for the same cohort after Compound 25 or vehicle administration. [Figure 3]A compares disease incidence in vehicle-treated male SOD1G93A mice, mice treated with 10 mg / kg of Compound 25, or 30 mg / kg of Compound 25. B compares survival rates in vehicle-treated male SOD1G93A mice, mice treated with 10 mg / kg of Compound 25, or 30 mg / kg of Compound 25. [Figure 4A] 1 shows the benefit of chronic daily dosing of 30 mg / kg of Compound 25 compared to vehicle-treated mice in a litter-matched, sex-balanced survival efficacy study. The age at onset of neurological disease is illustrated. [Figure 4B] 1 shows the benefit of chronic daily dosing of 30 mg / kg of Compound 25 compared to vehicle-treated mice in a litter-matched, gender-balanced survival efficacy study. The prolonged survival period is illustrated. [Figure 4C] Figure 1 shows the benefit of chronic daily dosing of 30 mg / kg Compound 25 compared to vehicle-treated mice in a litter-matched, gender-balanced survival efficacy study. Improved weight maintenance in Compound 25-treated mice is shown. [Figure 4D] 1 shows the benefit of chronic daily dosing of 30 mg / kg of Compound 25 compared to vehicle-treated mice in a litter-matched, gender-balanced survival efficacy study, illustrating the difference in neurological disease progression. [Figure 5] Figure 1A illustrates the change from baseline in CMAP after 4 weeks of daily dosing in male SOD1G93A mice treated with 10 mg / kg or 30 mg / kg of Compound 9 compared to control mice. Figure 1B shows the percent change from baseline in the same cohort after dosing with Compound 9 or vehicle. [Figure 6] A compares disease incidence in vehicle-treated male SOD1G93A mice, mice treated with 10 mg / kg of compound 9, or 30 mg / kg of compound 25. B compares survival rates in vehicle-treated male SOD1G93A mice, mice treated with 10 mg / kg of compound 9, or 30 mg / kg of compound 9. [Figure 7]Figure A illustrates the change in CMAP from baseline after 3 weeks of daily administration of 10 mg / kg or 30 mg / kg of Compound 24 or vehicle (control) to male SOD1G93A mice. Figure B illustrates the percentage of baseline for the same cohort after Compound 24 or vehicle administration. [Figure 8] A compares disease incidence in vehicle-treated male SOD1G93A mice, mice treated with 10 mg / kg of compound 24, or 30 mg / kg of compound 24. B compares survival rates in vehicle-treated male SOD1G93A mice, mice treated with 10 mg / kg of compound 24, or 30 mg / kg of compound 24. [Figure 9] Figure A illustrates the change from baseline in CMAP after 4 weeks of daily administration of 10 mg / kg or 30 mg / kg of Compound 37 or vehicle (control) to male SOD1G93A mice. Figure B illustrates the percentage of baseline for the same cohort after Compound 37 or vehicle administration. [Figure 10] A compares disease incidence in vehicle-treated male SOD1G93A mice, mice treated with 10 mg / kg of compound 37, or mice treated with 30 mg / kg of compound 37. B compares survival rates in vehicle-treated male SOD1G93A mice, mice treated with 10 mg / kg of compound 37, or mice treated with 30 mg / kg of compound 37. [Figure 11A] 1 illustrates the plasma and spinal cord concentrations of Compound 25 in female mice over several hours after administration. [Figure 11B] This is a logarithmic representation of the data in Figure 11A. [Figure 12A] 1 illustrates the plasma and spinal cord concentrations of Compound 25 in male mice over several hours after administration. [Figure 12B] This is a logarithmic representation of the data in Figure 12A. [Figure 13A] 1 illustrates the plasma and spinal cord concentrations of Compound 34 in female mice over several hours after administration. [Figure 13B] This is a logarithmic representation of the data in Figure 13A. [Figure 14A] 1 illustrates the plasma and spinal cord concentrations of Compound 34 in male mice over several hours after administration. [Figure 14B] This is a logarithmic representation of the data in Figure 14A. [Figure 15A] 1 illustrates the plasma and spinal cord concentrations of Compound 32 in female mice over several hours after administration. [Figure 15B] This is a logarithmic representation of the data in Figure 15A. [Figure 16A] 1 illustrates the plasma and spinal cord concentrations of Compound 32 in male mice over several hours after administration. [Figure 16B] This is a logarithmic representation of the data in Figure 16A. [Figure 17A] 1 illustrates the plasma and spinal cord concentrations of Compound 29 in female mice over several hours after administration. [Figure 17B] This is a logarithmic representation of the data in Figure 17A. [Figure 18A] 1 illustrates the plasma and spinal cord concentrations of Compound 29 in male mice over several hours after administration. [Figure 18B] This is a logarithmic representation of the data in Figure 18A. [Figure 19A] 1 illustrates the survival rate of female SOD1G93A mice treated with Compound 25 compared to controls. [Figure 19B] 1 illustrates the survival rate of male SOD1G93A mice treated with Compound 25 compared to controls. [Figure 20A] 1 illustrates the survival rate of female SOD1G93A mice treated with Compound 34 compared to controls. [Figure 20B] 1 illustrates the survival rate of male SOD1G93A mice treated with Compound 34 compared to controls. [Figure 21A] 1 illustrates the survival rate of female SOD1G93A mice treated with Compound 32 compared to controls. [Figure 21B] 1 illustrates the survival rate of male SOD1G93A mice treated with Compound 32 compared to controls. DETAILED DESCRIPTION OF THE INVENTION

[0025] As used herein, compounds of formula (I): [ka] and pharmaceutically acceptable salts thereof, a compound of formula (II): [ka] and pharmaceutically acceptable salts thereof, a compound of formula (III): [ka] and pharmaceutically acceptable salts thereof, a compound of formula (IV): [ka] and pharmaceutically acceptable salts thereof, and compounds of formula (V): [ka] and pharmaceutically acceptable salts thereof, all of which are useful in the treatment of neurological diseases and / or copper deficiency-related disorders.

[0026] definition Listed below are definitions of various terms used herein. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances either individually or as part of a larger group.

[0027] Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the nomenclature used herein and laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are those well known and commonly employed in the art.

[0028] As used herein, the articles "a" and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element. Furthermore, use of the term "including" as well as other forms such as "include," "includes," and "including" are not limiting.

[0029] As used herein, the term "about" will be understood by one of ordinary skill in the art and will vary to some extent depending on the context in which it is used. When used herein in reference to a measurable value such as an amount, length of time, etc., the term "about" is intended to encompass variations of ±20% or ±10% (including ±5%, ±1%, and ±0.1%) from the specified value, as such variations are appropriate in performing the disclosed methods.

[0030] As used in this specification and claims, the term "comprising" may include "consisting of" and "consisting essentially of" embodiments. As used herein, the terms "comprise(s)," "include(s)," "having," "has," "may," "containing," and variations thereof are intended to be open-ended transitional phrases, terms, or phrases that require the presence of the recited components / steps, and allow for the presence of other components / steps. However, such statements should also be construed as describing compositions or processes that "consist of" and "consist essentially of" the recited compounds, together with any pharmaceutically acceptable carriers, allowing for the presence of only the recited compounds, and excluding other compounds.

[0031] As used herein, the term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon having the specified number of carbon atoms (i.e., C1-C6 alkyl means an alkyl having 1 to 6 carbon atoms), including straight and branched chains. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, and 1-hexyl.

[0032] As used herein, the term "haloalkyl" refers to an alkyl group, as defined above, substituted with one or more halo substituents, where alkyl and halo are as defined herein. Haloalkyl includes, by way of example, chloromethyl, trifluoromethyl, bromoethyl, chlorofluoroethyl, and the like.

[0033] As used herein, the term "alkoxy" refers to the group -O-alkyl, where alkyl is as defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy, and the like.

[0034] The terms “halo” or “halogen,” as used herein, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. As used herein, the term "cycloalkyl" means a partially or fully saturated non-aromatic carbocyclic ring system having the specified number of carbon atoms. Cycloalkyl groups can be monocyclic, fused polycyclic, bridged polycyclic, or spiropolycyclic carbocyclic compounds. The term "cycloalkyl" includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[3.1.0]hexyl, spiro[3.3]heptanyl, and bicyclo[1.1.1]pentyl.

[0035] As used herein, the term "heterocyclyl" or "heterocycloalkyl" means a non-aromatic saturated or partially saturated monocyclic, fused polycyclic, bridged polycyclic, or spiro polycyclic ring system containing the specified number of ring atoms, wherein the ring atoms are carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. The term "heterocyclyl" includes cyclic esters (i.e., lactones) and cyclic amides (i.e., lactams), and also includes epoxidyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl (i.e., oxanyl), pyranyl, dioxanyl, aziridinyl, azetidinyl, pyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, oxazolidinyl, thiazolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, 1,3-oxazinanyl, 1,3-thiazinanyl, 2-azabicyclo[2.1.1]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 6-azabicyclo[3.1.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 2-azabicyclo[2.2.1]hexanyl, 3-azabicyclo[3.1.1]heptanyl, 2-azabicyclo[2.2.1]hexanyl, 2-azabicyclo[2.2.1]hept ...2-azabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2. Azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.0]hexanyl, 2-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 3-oxa-7-azabicyclo[3.3.1]nonanyl, 3-oxa-9-azabicyclo[3.3.1]nonanyl, 2-oxa-5-azabicyclo[2.2. Examples of heterocyclic or heterocycloalkyl groups include, but are not limited to, 2-oxaspiro[3.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, 2-oxaspiro[3.5]nonanyl, 3-oxaspiro[5.3]nonanyl, and 8-oxabicyclo[3.2.1]octanyl. Unless otherwise noted, the heterocycle or heterocycloalkyl is attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.

[0036] As used herein, the term "aromatic" refers to a carbocyclic or heterocyclic ring that contains one or more polyunsaturated rings and has aromatic properties, i.e., has (4n+2) delocalized π (pi) electrons, where n is an integer.

[0037] As used herein, the term "aryl" refers to an aromatic carbocyclic ring system containing the specified number of ring atoms. An aryl group can be a single ring or multiple rings (up to three rings) that are fused or covalently linked together. If rings are fused, one of the rings must be fully unsaturated, and the fused ring(s) may be fully saturated, partially unsaturated, or fully unsaturated. The term "aryl" includes, but is not limited to, phenyl, naphthyl, indanyl, and 1,2,3,4-tetrahydronaphthalenyl.

[0038] As used herein, the term "heteroaryl" means an aromatic carbocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. A heteroaryl group may be a single ring or multiple rings (up to 3 rings) fused or covalently linked together. If rings are fused, one of the rings must be fully unsaturated, and the fused ring(s) may be fully saturated, partially unsaturated, or fully unsaturated. The term "heteroaryl" includes but is not limited to furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, benzo[d][1,3]dioxolyl, 5,6,7,8-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, 6,7-dihydro-5H-cyclopenta[c]pyridinyl, and 5,6,7,8-tetrahydroisoquinolinyl. Examples of heterocyclic heterocyclic heterocyclic heterocyclic heteroaryl include, but are not limited to, pyridinyl, 1,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 2,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazolyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, 4,5,6,7-tetrahydro-1H-indazolyl, and 4,5,6,7-tetrahydro-2H-indazolyl. Unless otherwise noted, the heterocycle or heterocycloalkyl is attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.

[0039] As used herein, the term "substituted" means that an atom or group of atoms replaces a hydrogen as a substituent bonded to another group.

[0040] "Pharmaceutically acceptable salt" is intended to mean a free acid or base salt of a compound of the present disclosure that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject. It should possess the desired pharmacological activity of the parent compound. See generally G.S. Paulekuhn, et al., "Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database," J. Med. Chem., 2007, 50:6665-72; S.M. Berge, et al., "Pharmaceutical Salts," J. Pharm Sci., 1977, 66:1-19; and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002.

[0041] The term "treatment" refers to the application of one or more specific procedures used to ameliorate a disease. In certain embodiments, the specific procedure is the administration of one or more pharmaceutical agents. "Treatment" of an individual (e.g., a mammal such as a human) or cell is any type of intervention used in an attempt to alter the natural course of the individual or cell. Treatment includes, but is not limited to, the administration of a pharmaceutical composition and may be performed either prophylactically or following the onset of a pathological event or contact with a pathogen. Treatment includes any desired effect on the symptoms or pathology of a disease or condition, and may include, for example, a minimal change or improvement in one or more measurable markers of the disease or condition being treated.

[0042] As used herein, the term "prevent" or "prevention" means the absence of onset of a disorder or disease where none existed, or the absence of further onset of a disorder or disease where onset of a disorder or disease has already occurred. Also considered is the ability to prevent some or all of the symptoms associated with a disorder or disease.

[0043] As used herein, the term "use" includes any one or more of the following embodiments of the invention, respectively: use in the treatment of pain, use for the manufacture of a pharmaceutical composition for use in the treatment of these diseases, e.g., use in the manufacture of a medicament, unless otherwise specified, as appropriate and convenient; methods of using a compound of the invention in the treatment of these diseases; pharmaceutical preparations having a compound of the invention for the treatment of these diseases; and compounds of the invention for use in the treatment of these diseases.

[0044] As used herein, the terms "patient," "individual," or "subject" are intended to include organisms, e.g., prokaryotic and eukaryotic, that suffer from or are capable of suffering from a disease, disorder, or condition associated with protein kinase activity. Examples of subjects include mammals, e.g., humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In certain embodiments, the subject is a human, e.g., a human suffering from, at risk of, or potentially capable of suffering from ALS. In another embodiment, the subject is a cell. The terms "patient," "individual," or "subject" do not denote a particular age or sex.

[0045] As used in reference to the therapeutic / prophylactic methods and uses of the compounds and pharmaceutical compositions thereof described herein, an individual "in need" can be an individual who has been diagnosed with or previously treated for the condition being treated. With respect to prevention, an individual in need can also be an individual who is at risk for the condition (e.g., family history of the condition, lifestyle factors indicative of risk for the condition, etc.). Typically, where a step of administering a compound of the invention is disclosed herein, the invention further contemplates the step of identifying an individual or subject in need of the particular treatment to be administered or having the particular condition to be treated.

[0046] As used herein, the terms "effective amount," "pharmaceutically effective amount," and "therapeutically effective amount" refer to a nontoxic but sufficient amount of an agent to provide a desired biological result. That result may be a reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. The appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

[0047] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound useful within the present invention with a pharmaceutically acceptable diluent, excipient, or carrier. A pharmaceutical composition facilitates administration of a compound to a patient or subject. Multiple techniques for administering a compound exist in the art, including, but not limited to, intravenous, oral, aerosol, parenteral, intraocular, pulmonary, and topical administration.

[0048] As used herein, the terms "combination," "therapeutic combination," or "pharmaceutical combination" refer to either a fixed combination in a single unit dosage form, or a non-fixed combination, or a kit of parts for combined administration, in which two or more therapeutic agents can be administered independently, simultaneously or separately within time intervals, especially when these time intervals allow the combination partners to exhibit a cooperative (e.g., synergistic) effect.

[0049] The term "sporadic" refers to a neurodegenerative disease (e.g., ALS) that is not hereditary. Sporadic ALS accounts for approximately 90% of cases, in which the affected individual is the only member of the family with the disease. The cause of sporadic ALS is not fully understood but may result from a combination of environmental and genetic risk factors.

[0050] The term "familial" refers to a neurodegenerative disease (e.g., ALS) that is hereditary. Familial ALS accounts for approximately 10% of cases, in which two or more members of a family have ALS, and family members may also have frontotemporal dementia. People with familial ALS often begin to show symptoms at an earlier age than those with sporadic ALS. Familial ALS is most often autosomal dominant.

[0051] Compounds of the Disclosure In one aspect, provided herein is a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: L is C3-C7 cycloalkyl, C1-C6 alkyl, or absent; R1 is a 5- to 10-membered heteroaryl, C1-C6 alkyl optionally substituted with NH2, NH(C1-C6 alkyl), or N(C1-C6 alkyl)2; R2 is a 5- to 10-membered heteroaryl, C1-C6 alkyl optionally substituted with NH2, NH(C1-C6 alkyl), or N(C1-C6 alkyl)2; R3 is C6~C 10 aryl, 5- to 10-membered heteroaryl, C(O)NH—(C1-C6 alkyl)-PPh3, hydroxy, C1-C6 alkoxy, or O—(C1-C6 alkyl)-O—(C1-C6 alkyl), where C6-C 10 The aryl is a group R 3a and the 5- to 10-membered heteroaryl is optionally substituted with a group R 3b is substituted once, twice, or three times with R 3a is independently at each occurrence a C3-C7 cycloalkyl or a 4- to 8-membered heterocycle, wherein the 4- to 8-membered heterocycle is optionally further substituted once, twice, or three times with a C1-C3 alkyl; R 3b is independently at each occurrence C1-C3 alkoxy, C3-C7 cycloalkyl, or a 4- to 8-membered heterocycle, wherein the heterocycle is optionally further substituted once, twice, or three times with C1-C3 alkyl; R4 is hydrogen, C1-C3 alkyl, or C6-C 10 Although it is aryl, provided that when L is absent, R3 is a group R 3a C6-C substituted once, twice, or three times 10 aryl, or when L is absent, R3 is a group R 3b provided that the heteroaryl is a 6- to 10-membered heteroaryl substituted once, twice, or three times with

[0052] In certain embodiments, L is C3-C7 cycloalkyl or C1-C6 alkyl. In certain embodiments, L is C3-C7 cycloalkyl. In certain embodiments, L is C1-C6 alkyl. In certain embodiments, L is C3-C5 cycloalkyl or C1-C3 alkyl. In certain embodiments, L is C3-C5 cycloalkyl. In certain embodiments, L is C1-C3 alkyl.

[0053] In certain embodiments, L is -CH2-. In certain embodiments, L is -CH2CH2-. In certain embodiments, L is -CH2CH2CH2-. In certain embodiments, L is -CH2CH2CH2CH2-. In certain embodiments, L is -CH(CH3)-. In certain embodiments, L is -CH(CH2CH3)-. In certain embodiments, L is -C(CH3)2-.

[0054] In certain embodiments, L is a C3-C7 cycloalkyl or a C3-C5 cycloalkyl, where the cycloalkyl group includes a quaternary carbon that forms the point of attachment to group R3 and the remainder of the scaffold. Thus, in certain embodiments, L is represented by one of the following groups: [ka]

[0055] In one embodiment, R is C 1-6 In one embodiment, R is C 1-3 In certain embodiments, R1 is alkyl. In certain embodiments, R1 is methyl or ethyl. In certain embodiments, R1 is methyl. In certain embodiments, R1 is ethyl.

[0056] In one embodiment, R2 is C 1-6 In one embodiment, R2 is C 1-3 In certain embodiments, R2 is alkyl. In certain embodiments, R2 is methyl or ethyl. In certain embodiments, R2 is methyl. In certain embodiments, R2 is ethyl.

[0057] In certain embodiments, R1 and R2 are the same.

[0058] In one embodiment, R3 is C6-C 10 aryl, 6- to 10-membered heteroaryl, C(O)NH—(C1-C6 alkyl)-PPh3, hydroxy, C1-C6 alkoxy, or O—(C1-C6 alkyl)-O—(C1-C6 alkyl), where C6-C 10 Aryl is a group R 3a The 5- to 10-membered heteroaryl is optionally substituted with a group R 3b is substituted once, twice, or three times by

[0059] In certain embodiments, R3 is phenyl, pyridinyl, C(O)NH—(C1-C6 alkyl)-PPh3, hydroxy, C1-C6 alkoxy, or O—(C1-C6 alkyl)-O—(C1-C6 alkyl), where phenyl is selected from the group R 3a and pyridinyl is optionally substituted once, twice or three times with a group R 3b is substituted once, twice, or three times by

[0060] In certain embodiments, R3 is phenyl, pyridinyl, C(O)NH—(C1-C6 alkyl)-PPh3, hydroxy, C1-C6 alkoxy, or O—(C1-C6 alkyl)-O—(C1-C6 alkyl), where phenyl is selected from the group R 3a and pyridinyl is optionally substituted once with a group R 3b is replaced once by

[0061] In one embodiment, R 3a is independently at each occurrence a 4- to 8-membered heterocycle optionally further substituted once, twice, or three times with C1-C3 alkyl. 3a is independently at each occurrence a 4- to 8-membered heterocycle optionally further substituted once with methyl.

[0062] In one embodiment, R 3a is independently at each occurrence pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, or piperazinyl, each of which is optionally further substituted once, twice, or three times with C1-C3 alkyl. 3a is independently at each occurrence pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, or piperazinyl, each of which is optionally further substituted once with methyl. 3a is independently at each occurrence pyrrolidinyl, pyrrolidinonyl, or morpholinyl. 3a is represented independently at each occurrence by a group selected from: [ka]

[0063] In one embodiment, R 3b is independently at each occurrence a C1-C3 alkoxy or a 4- to 8-membered heterocycle, wherein the heterocycle is optionally further substituted once, twice, or three times with a C1-C3 alkyl. 3b is independently at each occurrence a C1-C3 alkoxy or a 4- to 8-membered heterocycle, wherein the heterocycle is optionally further substituted once with methyl.

[0064] In one embodiment, R 3b is independently at each occurrence C1-C3 alkoxy or a heterocycle selected from the group consisting of pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, and piperazinyl, wherein the heterocycle is optionally further substituted once, twice, or three times with C1-C3 alkyl. 3b is independently at each occurrence C1-C3 alkoxy or a heterocycle selected from the group consisting of pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, and piperazinyl, wherein the heterocycle is optionally further substituted once with methyl. 3b is, independently at each occurrence, methoxy or a heterocycle selected from the group consisting of pyrrolidinyl and morpholinyl. 3b is represented independently at each occurrence by a group selected from: [ka]

[0065] In certain embodiments, R4 is hydrogen, C1-C3 alkyl, or phenyl. In certain embodiments, R4 is hydrogen, methyl, or phenyl. In certain embodiments, R4 is hydrogen or C1-C3 alkyl. In certain embodiments, R4 is hydrogen or methyl. In certain embodiments, R4 is hydrogen. In certain embodiments, R4 is methyl. In certain embodiments, R4 is phenyl.

[0066] In certain embodiments, the group represented by R3-L has one of the following structures: [ka]

[0067] In certain embodiments, R3 is pyridinyl optionally substituted once, twice, or three times with C1-C3 alkoxy or a 4- to 8-membered heterocycle, wherein the 4- to 8-membered heterocycle is optionally substituted once with C1-C3 alkyl.

[0068] In certain embodiments, L is absent and R3 is pyridinyl substituted once, twice, or three times with C1-C3 alkoxy.

[0069] In certain embodiments, L is absent and R3 is phenyl substituted with a 4- to 8-membered heterocycle.

[0070] In one embodiment, L is C3-C5 cycloalkyl or C1-C3 alkyl, R3 is pyridinyl optionally substituted once, twice, or three times with a 4-8 membered heterocycle, and R4 is methyl.

[0071] In one embodiment, the compound of Formula (I) has the structure of compound 9: [ka]

[0072] Exemplary compounds of formula (I) include those set forth below, or a pharmaceutically acceptable salt thereof: [ka] [ka]

[0073] In another aspect, provided herein is a compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein: R1 is a 5- to 10-membered heteroaryl, C1-C6 alkyl optionally substituted with NH2, NH(C1-C6 alkyl), or N(C1-C6 alkyl)2; R2 is a 5- to 10-membered heteroaryl, C1-C6 alkyl optionally substituted with NH2, NH(C1-C6 alkyl), or N(C1-C6 alkyl)2; R3 is a 4- to 8-membered heterocycle or a 5-membered heteroaryl, wherein the 4- to 8-membered heterocycle optionally contains a group R 3a and the 5-membered heteroaryl is optionally substituted with a group R 3b is substituted once, twice, or three times with R 3a independently at each occurrence, C1-C6 alkyl, C1-C6 alkyl-(C6-C 10 aryl), S(O)2H, S(O)2-(C1-C6 alkyl), S(O)2-(C3-C7 cycloalkyl), or S(O)2-(C6-C 10 aryl), R 3b is independently at each occurrence C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, halo, nitro, cyano, C(O)-(4- to 8-membered heterocycle), or C1-C6 alkyl-(4- to 8-membered heterocycle), wherein each 4- to 8-membered heterocycle is optionally further substituted once, twice, or three times with C1-C3 alkyl; R4 is hydrogen or C 1-3 It is alkyl.

[0074] In one embodiment, R is C 1-6 In one embodiment, R is C 1-3 In certain embodiments, R1 is alkyl. In certain embodiments, R1 is methyl or ethyl. In certain embodiments, R1 is methyl. In certain embodiments, R1 is ethyl.

[0075] In one embodiment, R2 is C 1-6 In one embodiment, R2 is C 1-3 In certain embodiments, R2 is alkyl. In certain embodiments, R2 is methyl or ethyl. In certain embodiments, R2 is methyl. In certain embodiments, R2 is ethyl.

[0076] In certain embodiments, R1 and R2 are the same.

[0077] In certain embodiments, R3 is a 6-membered heterocycle or a 5-membered heteroaryl, wherein the 6-membered heterocycle optionally contains a group R 3a The 5-membered heteroaryl is optionally substituted with a group R 3b is substituted once, twice, or three times by

[0078] In certain embodiments, R3 is morpholinyl, piperidinyl, furyl, thiophenyl, or pyrazolyl, wherein morpholinyl and piperidinyl are optionally joined to a group R 3a and furyl, thiophenyl, and pyrazolyl are optionally substituted once, twice, or three times with a group R 3b is substituted once, twice, or three times by

[0079] In certain embodiments, R3 is a group R 3b In certain embodiments, R is a furyl, thiophenyl, or pyrazolyl optionally substituted once, twice, or three times with the group R 3bfuryl, thiophenyl, or pyrazolyl, substituted once, twice, or three times by

[0080] In certain embodiments, R3 is a group R 3b In certain embodiments, R is a furyl optionally substituted once, twice, or three times with the group R 3b is a fril substituted once, twice, or three times with

[0081] In certain embodiments, R3 is a group R 3a morpholinyl or piperidinyl optionally substituted once, twice or three times by

[0082] In one embodiment, R 3a is independently at each occurrence C1-C6 alkyl, C1-C6 alkyl-(C6-C 10 aryl), S(O)2-(C1-C6 alkyl), or S(O)2-(C6-C 10 aryl).

[0083] In one embodiment, R 3a is independently at each occurrence C1-C6 alkyl, C1-C6 alkyl-(phenyl), S(O)2-(C1-C6 alkyl), or S(O)2-(phenyl).

[0084] In one embodiment, R 3a is represented independently at each occurrence by a group selected from: [ka]

[0085] In one embodiment, R 3b is independently at each occurrence C1-C6 alkyl, halo, nitro, C(O)-(4- to 8-membered heterocycle), or C1-C6 alkyl-(4- to 8-membered heterocycle), where each 4- to 8-membered heterocycle is optionally further substituted once, twice, or three times with C1-C3 alkyl.

[0086] In one embodiment, R3b is independently at each occurrence C1-C6 alkyl, halo, nitro, C(O)-(4- to 8-membered heterocycle), or C1-C6 alkyl-(4- to 8-membered heterocycle), wherein each 4- to 8-membered heterocycle is independently selected from the group consisting of pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, and piperazinyl, and each 4- to 8-membered heterocycle is optionally further substituted once, twice, or three times with C1-C3 alkyl.

[0087] In one embodiment, R 3b is independently at each occurrence C1-C6 alkyl, halo, nitro, C(O)-(4- to 8-membered heterocycle), or C1-C6 alkyl-(4- to 8-membered heterocycle), where each 4- to 8-membered heterocycle is independently selected from the group consisting of morpholinyl, piperidinyl, and piperazinyl, and each 4- to 8-membered heterocycle is optionally further substituted once, twice, or three times with methyl.

[0088] In one embodiment, R 3b is represented independently at each occurrence by a group selected from: [ka] In certain embodiments, R4 is hydrogen or methyl. In certain embodiments, R4 is hydrogen. In certain embodiments, R4 is methyl.

[0089] In certain embodiments, R3 is furyl substituted once, twice, or three times with C(O)-(4- to 8-membered heterocycle) or C1-C6 alkyl-(4- to 8-membered heterocycle), where each 4- to 8-membered heterocycle is optionally further substituted once, twice, or three times with C1-C3 alkyl.

[0090] In certain embodiments, R3 is furyl substituted once, twice, or three times with C(O)-(4- to 8-membered heterocycle) or C1-C6 alkyl-(4- to 8-membered heterocycle), wherein each 4- to 8-membered heterocycle is independently selected from the group consisting of pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, and piperazinyl, and each 4- to 8-membered heterocycle is optionally further substituted once, twice, or three times with C1-C3 alkyl.

[0091] In certain embodiments, R3 is furyl substituted once, twice, or three times with C(O)-(4- to 8-membered heterocycle) or C1-C6 alkyl-(4- to 8-membered heterocycle), where each 4- to 8-membered heterocycle is independently selected from the group consisting of morpholinyl, piperidinyl, and piperazinyl, and each 4- to 8-membered heterocycle is optionally further substituted once, twice, or three times with C1-C3 alkyl.

[0092] In certain embodiments, R3 is furyl substituted once, twice, or three times with C(O)-(morpholinyl) or C1-C6 alkyl-(morpholinyl).

[0093] In certain embodiments, R3 is represented by a group selected from the following: [ka]

[0094] In one embodiment, the compound of Formula (II) has the structure of compound 24: [ka]

[0095] In one embodiment, the compound of Formula (II) has the structure of compound 25: [ka]

[0096] In one embodiment, the compound of Formula (II) has the structure of compound 37: [ka]

[0097] Exemplary compounds of formula (II) include those set forth below, or pharmaceutically acceptable salts thereof: [ka] [ka] [ka]

[0098] In yet another aspect, provided herein is a compound of formula (III): [ka] or a pharmaceutically acceptable salt thereof, wherein: L is C1-C6 alkyl or absent; R1 is a 5- to 10-membered heteroaryl, C1-C6 alkyl optionally substituted with NH2, NH(C1-C6 alkyl), or N(C1-C6 alkyl)2; R2 is a 5- to 10-membered heteroaryl, C1-C6 alkyl optionally substituted with NH2, NH(C1-C6 alkyl), or N(C1-C6 alkyl)2; R3 is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, halo, hydroxy, C(O)NH2, C(O)NH(C1-C6 alkyl), C(O)N(C1-C6 alkyl)2, or C(O)-(4- to 8-membered heterocycle), wherein C1-C6 alkyl and C1-C6 alkoxy are optionally C6-C 10The C(O)-(4- to 8-membered heterocycle) is optionally substituted once, twice, or three times with C1-C3 alkyl.

[0099] In some embodiments, L is C1-C3 alkyl or absent. In some embodiments, L is C1-C3 alkyl. In some embodiments, L is absent.

[0100] In certain embodiments, R1 is C1-C6 alkyl optionally substituted with NH2, NH(C1-C6 alkyl), or N(C1-C6 alkyl). In certain embodiments, R1 is C1-C6 alkyl optionally substituted with N(C1-C6 alkyl). In certain embodiments, R1 is C1-C3 alkyl optionally substituted with N(C1-C3 alkyl). In certain embodiments, R1 is methyl or ethyl, where ethyl is optionally substituted with N(CH2CH3).

[0101] In certain embodiments, R2 is C1-C6 alkyl optionally substituted with NH2, NH(C1-C6 alkyl), or N(C1-C6 alkyl). In certain embodiments, R2 is C1-C6 alkyl optionally substituted with N(C1-C6 alkyl). In certain embodiments, R2 is C1-C3 alkyl optionally substituted with N(C1-C3 alkyl). In certain embodiments, R2 is methyl or ethyl, where ethyl is optionally substituted with N(CH2CH3).

[0102] In certain embodiments, R1 and R2 are the same.

[0103] In certain embodiments, R3 is C1-C6 alkyl, C1-C6 alkoxy, hydroxy, or C(O)-(4- to 8-membered heterocycle), wherein C1-C6 alkyl and C1-C6 alkoxy are optionally C6-C6 alkyl, C1-C6 alkoxy, or C(O)-(4- to 8-membered heterocycle). 10 It is substituted once with aryl, and C(O)-(4- to 8-membered heterocycle) is optionally substituted once with C1-C3 alkyl.

[0104] In certain embodiments, R3 is C1-C3 alkyl, C1-C3 alkoxy, hydroxy, or C(O)-(6-membered heterocycle), wherein C1-C3 alkyl and C1-C3 alkoxy are optionally substituted once with phenyl.

[0105] In certain embodiments, R3 is C1-C3 alkyl, C1-C3 alkoxy, hydroxy, or C(O)-(morpholinyl), wherein C1-C3 alkyl and C1-C3 alkoxy are optionally substituted once with phenyl.

[0106] In certain embodiments, the group represented by R3-L has one of the following structures: [ka]

[0107] In some embodiments, L is absent and R3 is C1-C6 alkyl.

[0108] Exemplary compounds of formula (III) include those set forth below, or pharmaceutically acceptable salts thereof: [ka]

[0109] In another aspect, provided herein is a compound of formula (IV): [ka] or a pharmaceutically acceptable salt thereof, wherein: L is C3-C7 cycloalkyl, C1-C6 alkyl, or absent; R1 is a 5- to 10-membered heteroaryl, C1-C6 alkyl optionally substituted with NH2, NH(C1-C6 alkyl), or N(C1-C6 alkyl)2; R2 is a 5- to 10-membered heteroaryl, C1-C6 alkyl optionally substituted with NH2, NH(C1-C6 alkyl), or N(C1-C6 alkyl)2; R3 is C6~C 10 Aryl, 5- to 10-membered heteroaryl, C3-C 10 cycloalkyl, C(O)NH—(C1-C6 alkyl)-PPh3, hydroxy, C1-C6 alkoxy, or O—(C1-C6 alkyl)-O—(C1-C6 alkyl), where C6-C 10 The aryl is a group R 3a and the 5- to 10-membered heteroaryl is optionally substituted with a group R 3b is substituted once, twice, or three times with R 3a is independently at each occurrence a C3-C7 cycloalkyl or a 4- to 8-membered heterocycle, wherein the 4- to 8-membered heterocycle is optionally further substituted once, twice, or three times with a C1-C3 alkyl; R 3b is independently at each occurrence C1-C3 alkyl, C1-C3 alkoxy, C3-C7 cycloalkyl, or a 4- to 8-membered heterocycle, wherein the heterocycle is optionally further substituted once, twice, or three times with C1-C3 alkyl; R4 is hydrogen, C1-C3 alkyl, or C6-C 10 Although it is aryl, provided that when L is absent, R3 is a group R 3a C6-C substituted once, twice, or three times 10 aryl, or when L is absent, R3 is a group R 3b or when L is absent, R3 is a group R 3b provided that R4 is H.

[0110] In certain embodiments, L is C3-C7 cycloalkyl or C1-C6 alkyl. In certain embodiments, L is C3-C7 cycloalkyl. In certain embodiments, L is C1-C6 alkyl. In certain embodiments, L is C3-C5 cycloalkyl or C1-C3 alkyl. In certain embodiments, L is C3-C5 cycloalkyl. In certain embodiments, L is C1-C3 alkyl.

[0111] In certain embodiments, L is -CH2-. In certain embodiments, L is -CH2CH2-. In certain embodiments, L is -CH2CH2CH2-. In certain embodiments, L is -CH2CH2CH2CH2-. In certain embodiments, L is -CH(CH3)-. In certain embodiments, L is -CH(CH2CH3)-. In certain embodiments, L is -C(CH3)2-.

[0112] In certain embodiments, L is a C3-C7 cycloalkyl or a C3-C5 cycloalkyl, where the cycloalkyl group includes a quaternary carbon that forms the point of attachment to group R3 and the remainder of the scaffold. Thus, in certain embodiments, L is represented by one of the following groups: [ka]

[0113] In one embodiment, R is C 1-6 In one embodiment, R is C 1-3 In certain embodiments, R1 is alkyl. In certain embodiments, R1 is methyl or ethyl. In certain embodiments, R1 is methyl. In certain embodiments, R1 is ethyl.

[0114] In certain embodiments, R1 is C1-C6 alkyl optionally substituted with 5-membered heteroaryl. In certain embodiments, R1 is C1-C6 alkyl optionally substituted with furyl. In certain embodiments, R1 is CH2-furyl.

[0115] In one embodiment, R2 is C 1-6 In one embodiment, R2 is C 1-3 In certain embodiments, R2 is alkyl. In certain embodiments, R2 is methyl or ethyl. In certain embodiments, R2 is methyl. In certain embodiments, R2 is ethyl.

[0116] In certain embodiments, R2 is C1-C6 alkyl optionally substituted with 5-membered heteroaryl. In certain embodiments, R2 is C1-C6 alkyl optionally substituted with furyl. In certain embodiments, R2 is CH2-furyl.

[0117] In certain embodiments, R1 and R2 are the same.

[0118] In one embodiment, R3 is C6-C 10 Aryl, 5- to 10-membered heteroaryl, C3-C 10 cycloalkyl, or C1-C6 alkoxy, where C6-C 10 Aryl is a group R 3a The 5- to 10-membered heteroaryl is optionally substituted with a group R 3b is substituted once, twice, or three times by

[0119] In certain embodiments, R3 is a 5- to 10-membered heteroaryl or a C3-C 10 cycloalkyl, where the 5- to 10-membered heteroaryl is optionally selected from the group R 3b is substituted once, twice, or three times by

[0120] In certain embodiments, R3 is phenyl, pyrazolyl, pyridinyl, benzofuranyl, benzothiazolyl, benzodioxolyl, C3-C6 cycloalkyl, adamantyl, C(O)NH—(C1-C6 alkyl)-PPh3, hydroxy, C1-C6 alkoxy, or O—(C1-C6 alkyl)-O—(C1-C6 alkyl), where phenyl is selected from the group R 3apyrazolyl, pyridinyl, benzofuranyl, benzothiazolyl, and benzodioxolyl are optionally substituted once, twice, or three times by a group R 3b is substituted once, twice, or three times by

[0121] In certain embodiments, R3 is phenyl, pyrazolyl, pyridinyl, benzofuranyl, benzothiazolyl, benzodioxolyl, or C1-C6 alkoxy, wherein pyrazolyl, pyridinyl, benzofuranyl, benzothiazolyl, and benzodioxolyl are optionally substituted with a group R 3b is substituted once or twice by

[0122] In certain embodiments, R3 is pyridinyl, benzofuranyl, or benzodioxolyl, where pyridinyl, benzofuranyl, and benzodioxolyl are optionally substituted with a group R 3b is substituted once or twice by

[0123] In certain embodiments, R3 is benzofuranyl or benzodioxolyl, where benzofuranyl and benzodioxolyl optionally contain a group R 3b is substituted once or twice by

[0124] In one embodiment, R 3a is independently at each occurrence a 4- to 8-membered heterocycle optionally further substituted once, twice, or three times with C1-C3 alkyl. 3a is independently at each occurrence a 4- to 8-membered heterocycle optionally further substituted once with methyl.

[0125] In one embodiment, R 3a is independently at each occurrence pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, or piperazinyl, each of which is optionally further substituted once, twice, or three times with C1-C3 alkyl. 3ais independently at each occurrence pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, or piperazinyl, each of which is optionally further substituted once with methyl. 3a is independently at each occurrence pyrrolidinyl, pyrrolidinonyl, or morpholinyl. 3a is represented independently at each occurrence by a group selected from: [ka]

[0126] In one embodiment, R 3b is independently at each occurrence C1-C3 alkyl, C1-C3 alkoxy, or a 4- to 8-membered heterocycle, wherein the heterocycle is optionally further substituted once, twice, or three times with C1-C3 alkyl. 3b is independently at each occurrence a C1-C3 alkoxy or a 4- to 8-membered heterocycle, wherein the heterocycle is optionally further substituted once with methyl.

[0127] In one embodiment, R 3b is independently at each occurrence C1-C3 alkyl, C1-C3 alkoxy, or a heterocycle selected from the group consisting of pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, and piperazinyl, wherein the heterocycle is optionally further substituted once, twice, or three times with C1-C3 alkyl. 3b is independently at each occurrence C1-C3 alkyl, C1-C3 alkoxy, or a heterocycle selected from the group consisting of pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, and piperazinyl, wherein the heterocycle is optionally further substituted once with methyl. 3bis independently at each occurrence methyl, methoxy, or a heterocycle selected from the group consisting of pyrrolidinyl and morpholinyl. 3b is expressed independently for each occurrence as [ka] is represented by a group selected from:

[0128] In certain embodiments, R4 is hydrogen, C1-C3 alkyl, or phenyl. In certain embodiments, R4 is hydrogen, methyl, or phenyl. In certain embodiments, R4 is hydrogen or C1-C3 alkyl. In certain embodiments, R4 is hydrogen or methyl. In certain embodiments, R4 is hydrogen. In certain embodiments, R4 is methyl. In certain embodiments, R4 is phenyl.

[0129] In certain embodiments, L is C1-C6 alkyl and R3 is C1-C6 alkoxy.

[0130] In certain embodiments, the group represented by R3-L is represented by one of the following: [ka]

[0131] In certain embodiments, the group represented by R3-L is represented by one of the following: [ka]

[0132] In certain embodiments, R3 is pyridinyl optionally substituted once, twice, or three times with C1-C3 alkoxy or a 4- to 8-membered heterocycle, wherein the 4- to 8-membered heterocycle is optionally substituted once with C1-C3 alkyl.

[0133] In one embodiment, when L is absent, R3 is a group R3a C6-C substituted once, twice, or three times 10 aryl, or when L is absent, R3 is a group R 3b In another embodiment, when L is absent, R3 is a 6- to 10-membered heteroaryl substituted once, twice, or three times with 3a C6-C substituted once, twice, or three times 10 aryl, or when L is absent, R3 is a group R 3b and R4 is H.

[0134] In certain embodiments, when L is absent, R3 is pyridinyl substituted once, twice, or three times with C1-C3 alkoxy.

[0135] In certain embodiments, when L is absent, R3 is phenyl substituted with a 4- to 8-membered heterocycle.

[0136] In one embodiment, when L is absent, R3 is a group R 3a C6-C substituted once, twice, or three times 10 aryl, or when L is absent, R3 is a group R 3b is a 6- to 10-membered heteroaryl substituted once, twice, or three times with

[0137] In one embodiment, L is C3-C5 cycloalkyl or C1-C3 alkyl, R3 is pyridinyl optionally substituted once, twice, or three times with a 4-8 membered heterocycle, and R4 is methyl.

[0138] Exemplary compounds of formula (IV) include the following compounds, or pharmaceutically acceptable salts thereof: [ka] [ka] [ka] [ka]

[0139] In certain embodiments, the compound of Formula (IV) is one of the following compounds, or a pharmaceutically acceptable salt thereof: [ka]

[0140] In certain embodiments, the compound of formula (IV) has the structure of Compound 2: [ka]

[0141] In one embodiment, the compound of Formula (IV) has the structure of compound 59: [ka]

[0142] In one embodiment, the compound of formula (IV) has the structure of compound 60: [ka]

[0143] In one embodiment, the compound of Formula (IV) has the structure of compound 61: [ka]

[0144] In one embodiment, the compound of Formula (IV) has the structure of compound 74: [ka]

[0145] In one embodiment, the compound of Formula (IV) has the structure of compound 74: [ka]

[0146] In another aspect, provided herein is a compound of formula (V): [ka] or a pharmaceutically acceptable salt thereof, wherein: R1 is a 5- to 10-membered heteroaryl, C1-C6 alkyl optionally substituted with NH2, NH(C1-C6 alkyl), or N(C1-C6 alkyl)2; R2 is a 5- to 10-membered heteroaryl, C1-C6 alkyl optionally substituted with NH2, NH(C1-C6 alkyl), or N(C1-C6 alkyl)2; R3 is a 4- to 8-membered heterocycle or a 5-membered heteroaryl, wherein the 4- to 8-membered heterocycle optionally contains a group R 3a and the 5-membered heteroaryl is optionally substituted with a group R 3b is substituted once, twice, or three times with R 3a independently at each occurrence, C1-C6 alkyl, C1-C6 alkyl-(C6-C 10 aryl), C1-C6 alkyl-(5- to 10-membered heteroaryl), S(O)2H, S(O)2-(C1-C6 alkyl), S(O)2-(C3-C7 cycloalkyl), or S(O)2-(C6-C 10 aryl), where each heteroaryl is optionally C1-C6 alkyl or C6-C 10 Further substituted 1 to 4 times with aryl, each C6 to C 10 the aryl is optionally further substituted 1 to 4 times with C1-C6 alkyl; R 3beach occurrence independently represents C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkyl-N(R5)2, (C1-C6 alkyl)-O-(C1-C6 alkyl), halo, nitro, cyano, C6-C 10 Aryl, C(O)-(4- to 8-membered heterocycle), C1-C6 alkyl-(C6-C 10 aryl), C1-C6 alkyl-(5- to 10-membered heteroaryl), or C1-C6 alkyl-(4- to 8-membered heterocycle), where each of the 4- to 8-membered heterocycle, C6-C 10 aryl, and 5- to 10-membered heteroaryl are optionally further substituted 1 to 4 times with C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or halo; R4 is hydrogen or C 1-3 is alkyl, R5, independently at each occurrence, is hydrogen, C1-C6 alkyl, or C1-C3 alkyl-(C6-C 10 aryl).

[0147] In one embodiment, R is C 1-6 In one embodiment, R is C 1-3 In certain embodiments, R1 is alkyl. In certain embodiments, R1 is methyl or ethyl. In certain embodiments, R1 is methyl. In certain embodiments, R1 is ethyl.

[0148] In certain embodiments, R1 is C1-C6 alkyl optionally substituted with 5-membered heteroaryl. In certain embodiments, R1 is C1-C6 alkyl optionally substituted with furyl. In certain embodiments, R1 is CH2-furyl.

[0149] In one embodiment, R2 is C 1-6 In one embodiment, R2 is C 1-3 In certain embodiments, R2 is alkyl. In certain embodiments, R2 is methyl or ethyl. In certain embodiments, R2 is methyl. In certain embodiments, R2 is ethyl.

[0150] In certain embodiments, R2 is C1-C6 alkyl optionally substituted with 5-membered heteroaryl. In certain embodiments, R2 is C1-C6 alkyl optionally substituted with furyl. In certain embodiments, R2 is CH2-furyl.

[0151] In certain embodiments, R1 and R2 are the same.

[0152] In certain embodiments, R3 is a 5- to 6-membered heterocycle or a 5-membered heteroaryl, wherein the 5- to 6-membered heterocycle optionally contains a group R 3a The 5-membered heteroaryl is optionally substituted with a group R 3b is substituted once, twice, or three times by

[0153] In certain embodiments, R3 is tetrahydrofuranyl, morpholinyl, piperidinyl, furyl, thiophenyl, pyrrolyl, oxazolyl, pyrazolyl, or imidazolyl, wherein tetrahydrofuranyl, morpholinyl, and piperidinyl are optionally substituted with a group R 3a furyl, thiophenyl, pyrrolyl, oxazolyl, pyrazolyl, and imidazolyl are optionally substituted once, twice, or three times with a group R 3b is substituted once, twice, or three times by

[0154] In certain embodiments, R3 is a group R 3b In another embodiment, R is a group R 3b furyl, thiophenyl, oxazolyl, pyrazolyl, or imidazolyl, substituted once, twice, or three times by

[0155] In certain embodiments, R3 is a group R 3b In another embodiment, R is a furyl optionally substituted once, twice, or three times with the group R 3b is a fril substituted once, twice, or three times with

[0156] In certain embodiments, R3 is a group R 3b In another embodiment, R3 is a group R 3b and thiophenyl substituted once, twice, or three times with

[0157] In certain embodiments, R3 is a group R 3b In another embodiment, R is oxazolyl optionally substituted once, twice, or three times with the group R 3b is an oxazolyl substituted once, twice, or three times with

[0158] In certain embodiments, R3 is a group R 3b In another embodiment, R is a group R 3b and pyrazolyl substituted once, twice, or three times with

[0159] In certain embodiments, R3 is a group R 3b In another embodiment, R is an imidazolyl optionally substituted once, twice, or three times with the group R 3b imidazolyl substituted once, twice, or three times with

[0160] In certain embodiments, R3 is tetrahydrofuranyl, morpholinyl, or piperidinyl, each of which optionally contains a group R 3a is substituted once, twice, or three times by

[0161] In one embodiment, R 3a is independently at each occurrence C1-C6 alkyl, C1-C6 alkyl-(C6-C 10 aryl), C1-C6 alkyl-(5-membered to 10-membered heteroaryl), S(O)2-(C1-C6 alkyl), or S(O)2-(C6-C 10 aryl), where each heteroaryl is optionally C1-C6 alkyl or C6-C 10 Further substituted 1 to 4 times with aryl, each C6 to C 10The aryl is optionally further substituted 1 to 4 times with C1-C6 alkyl.

[0162] In one embodiment, R 3a is independently at each occurrence C1-C6 alkyl, C1-C6 alkyl-(phenyl), C1-C6 alkyl-(5- to 6-membered heteroaryl), S(O)2-(C1-C6 alkyl), or S(O)2-(phenyl), where each heteroaryl is optionally further substituted 1 to 4 times with C1-C3 alkyl or phenyl, and each phenyl is optionally further substituted 1 to 4 times with C1-C3 alkyl.

[0163] In one embodiment, R 3a is expressed independently for each occurrence as [ka] is.

[0164] In one embodiment, R 3b is independently selected at each occurrence from C1-C6 alkyl, C1-C6 alkyl-N(R5)2, (C1-C6 alkyl)-O-(C1-C6 alkyl), halo, nitro, C6-C 10 Aryl, C(O)-(4- to 8-membered heterocycle), C1-C6 alkyl-(C6-C 10 aryl), C1-C6 alkyl-(5- to 10-membered heteroaryl), or C1-C6 alkyl-(4- to 8-membered heterocycle), where each of the 4- to 8-membered heterocycle, C6-C 10 The aryl and 5- to 10-membered heteroaryl are optionally further substituted 1 to 4 times with C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or halo.

[0165] In one embodiment, R 3b is independently selected at each occurrence from C1-C6 alkyl, C1-C6 alkyl-N(R5)2, halo, C6-C 10 Aryl, C1-C6 alkyl-(4-membered to 8-membered heterocycle), or C1-C6 alkyl-(C6-C 10 aryl), where each is a 4- to 8-membered heterocycle and a C6 to C10 The aryl is optionally further substituted 1 to 4 times with C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or halo.

[0166] In one embodiment, R 3b is independently at each occurrence C1-C6 alkyl, C1-C3 alkyl-N(R5)2, halo, phenyl, C1-C3 alkyl-(5- to 6-membered heterocycle), or C1-C6 alkyl-phenyl, wherein each 5- to 6-membered heterocycle and phenyl is optionally further substituted 1 to 4 times with C1-C3 alkyl or halo.

[0167] In one embodiment, R 3b is independently selected at each occurrence from C1-C6 alkyl, C1-C6 alkyl-N(R5)2, (C1-C6 alkyl)-O-(C1-C6 alkyl), halo, nitro, C6-C 10 Aryl, C(O)-(4- to 8-membered heterocycle), C1-C6 alkyl-(C6-C 10 aryl), C1-C6 alkyl-(5- to 10-membered heteroaryl), or C1-C6 alkyl-(4- to 8-membered heterocycle), where each of the 4- to 8-membered heterocycle, C6-C 10 The aryl and 5- to 10-membered heteroaryl are optionally further substituted 1 to 4 times with -CH3, -CH2CH3, -OCH3, -CH2F, CHF2, -CF3, -F, or -Cl.

[0168] In one embodiment, R 3bis independently at each occurrence C1-C6 alkyl, C1-C6 alkyl-N(R5)2, (C1-C6 alkyl)-O-(C1-C6 alkyl), halo, nitro, phenyl, C(O)-(4- to 8-membered heterocycle), C1-C6 alkyl-phenyl, C1-C6 alkyl-(5- to 10-membered heteroaryl), or C1-C6 alkyl-(4- to 8-membered heterocycle), wherein each 4- to 8-membered heterocycle is independently selected from pyrrolidinyl, pyrrolidinonyl, is selected from the group consisting of tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, and piperazinyl; each 5- to 10-membered heteroaryl is selected from the group consisting of furyl and tetrahydroisoquinolinyl; and each 4- to 8-membered heterocycle, phenyl, and 5- to 10-membered heteroaryl is optionally further substituted 1 to 4 times with -CH, -CHCH, -OCH, -CHF, CHF, -CF, -F, or -Cl.

[0169] In one embodiment, R 3b is independently at each occurrence C-C alkyl, C-C alkyl-N(R), (C-C alkyl)-O-(C-C alkyl), halo, nitro, phenyl, C(O)-(4- to 8-membered heterocycle), C-C alkyl-phenyl, C-C alkyl-(5- to 10-membered heteroaryl), or C-C alkyl-(4- to 8-membered heterocycle), wherein each 4- to 8-membered heterocycle is independently selected from the group consisting of pyrrolidinyl, morpholinyl, piperidinyl, and piperazinyl; each 5- to 10-membered heteroaryl is selected from the group consisting of furyl and tetrahydroisoquinolinyl; and each 4- to 8-membered heterocycle, phenyl, and 5- to 10-membered heteroaryl is optionally further substituted 1 to 4 times with -CH, -OCH, -CF, or -F.

[0170] In one embodiment, R 3b is expressed independently for each occurrence as [ka] is.

[0171] In one embodiment, R 3bis expressed independently for each occurrence as [ka] is.

[0172] In one embodiment, R 3b is expressed independently for each occurrence as [ka] is.

[0173] In one embodiment, R 3b is expressed independently for each occurrence as [ka] is.

[0174] In one embodiment, R 3b is expressed independently for each occurrence as [ka] is.

[0175] In certain embodiments, R3 is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkyl-N(R5), (C1-C6 alkyl)-O-(C1-C6 alkyl), halo, nitro, cyano, C6-C 10 Aryl, C(O)-(4- to 8-membered heterocycle), C1-C6 alkyl-(C6-C 10 aryl), C1-C6 alkyl-(5- to 10-membered heteroaryl), or C1-C6 alkyl-(4- to 8-membered heterocycle), where each of the 4- to 8-membered heterocycle, C6-C 10 The aryl and 5- to 10-membered heteroaryl are optionally further substituted 1 to 4 times with C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or halo.

[0176] In certain embodiments, R3 is furyl optionally substituted once, twice, or three times with C1-C6 alkyl, C1-C6 alkyl-N(R5)2, halo, C(O)-(4- to 8-membered heterocycle), or C1-C6 alkyl-(4- to 8-membered heterocycle), where each 4- to 8-membered heterocycle is optionally further substituted 1 to 4 times with C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or halo.

[0177] In certain embodiments, R3 is furyl optionally substituted once, twice, or three times with C1-C6 alkyl-N(R5)2 or C1-C6 alkyl-(4- to 8-membered heterocycle), where each 4- to 8-membered heterocycle is optionally further substituted 1 to 4 times with C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or halo.

[0178] In certain embodiments, R3 is furyl optionally substituted once with C1-C3 alkyl-N(C1-C4 alkyl)2 or C1-C3 alkyl-(5- to 6-membered heterocycle), where the 5- to 6-membered heterocycle is optionally further substituted 1 to 4 times with C1-C3 alkyl.

[0179] In certain embodiments, R3 is furyl substituted once with C1-C3 alkyl-N(C1-C4 alkyl)2 or C1-C3 alkyl-(5- to 6-membered heterocycle), where the 5- to 6-membered heterocycle is optionally further substituted 1 to 4 times with C1-C3 alkyl.

[0180] In one embodiment, R3 is C1-C6 alkyl, halo, C6-C 10 Aryl, or C1-C6 alkyl-(C6-C 10 aryl), wherein each C6-C 10 The aryl is optionally further substituted 1 to 4 times with C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or halo.

[0181] In certain embodiments, R3 is thiophenyl, oxazolyl, pyrazolyl, or imidazolyl optionally substituted once, twice, or three times with methyl, ethyl, halo, phenyl, or C1-C3 alkyl-phenyl, where each phenyl is optionally further substituted one to four times with C1-C3 alkyl or halo.

[0182] In one embodiment, R3 is [ka] [ka] is.

[0183] In one embodiment, R3 is [ka] is.

[0184] In one embodiment, R3 is [ka] is.

[0185] In one embodiment, R3 is [ka] is.

[0186] In one embodiment, R3 is [ka] is.

[0187] In certain embodiments, R4 is hydrogen or methyl. In certain embodiments, R4 is hydrogen. In certain embodiments, R4 is methyl.

[0188] In one embodiment, R5 is C1-C6 alkyl or C1-C3 alkyl-(C6-C 10 In another embodiment, R5 is C1-C4 alkyl or C1-C3 alkyl-phenyl. In another embodiment, R5 is C1-C4 alkyl or benzyl.

[0189] In one embodiment, when R1 is not methyl, R2 is not methyl, and R4 is not hydrogen, R 3b is independently selected at each occurrence from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkyl-N(R5)2, (C1-C6 alkyl)-O-(C1-C6 alkyl), halo, nitro, cyano, C6-C 10 Aryl, C(O)-(4- to 8-membered heterocycle), C1-C6 alkyl-(C6-C 10 aryl), C1-C6 alkyl-(5- to 10-membered heteroaryl), or C1-C6 alkyl-(4- to 8-membered heterocycle), where each of the 4- to 8-membered heterocycle, C6-C 10 The aryl and 5- to 10-membered heteroaryl are optionally further substituted once or twice with C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or halo.

[0190] In one embodiment, when R4 is not hydrogen, R 3b is independently selected at each occurrence from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkyl-N(R5)2, (C1-C6 alkyl)-O-(C1-C6 alkyl), halo, nitro, cyano, C6-C 10 Aryl, C(O)-(4- to 8-membered heterocycle), C1-C6 alkyl-(C6-C 10 aryl), C1-C6 alkyl-(5- to 10-membered heteroaryl), or C1-C6 alkyl-(4- to 8-membered heterocycle), where each of the 4- to 8-membered heterocycle, C6-C 10 The aryl and 5- to 10-membered heteroaryl are optionally further substituted once or twice with C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or halo.

[0191] In certain embodiments, when R3 is oxazolyl, R3 does not have the following structure: [ka]

[0192] In certain embodiments of the compound of Formula (V), or a pharmaceutically acceptable salt thereof, R1 is C1-C3 alkyl, R2 is C1-C3 alkyl, R3 is a group R 3b is a 5-membered heteroaryl optionally substituted once, twice, or three times by R 3b is independently selected at each occurrence from C1-C6 alkyl, C1-C6 alkyl-N(R5)2, (C1-C6 alkyl)-O-(C1-C6 alkyl), halo, C6-C 10 Aryl, C(O)-(4- to 8-membered heterocycle), C1-C6 alkyl-(C6-C 10 aryl), C1-C6 alkyl-(5- to 10-membered heteroaryl), or C1-C6 alkyl-(4- to 8-membered heterocycle), where each of the 4- to 8-membered heterocycle, C6-C 10 aryl, and 5- to 10-membered heteroaryl are optionally further substituted 1 to 4 times with C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or halo; R4 is hydrogen or methyl; R5 is, independently at each occurrence, C1-C4 alkyl or benzyl.

[0193] In another embodiment of the compound of Formula (V), or a pharmaceutically acceptable salt thereof, R1 is C1-C3 alkyl, R2 is C1-C3 alkyl, R3 is a group R 3b and R 3bis independently at each occurrence C1-C6 alkyl-N(R5)2 or C1-C6 alkyl-(4- to 8-membered heterocycle), wherein each 4- to 8-membered heterocycle is optionally further substituted 1 to 4 times with C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or halo; R4 is hydrogen or methyl; R5 is, independently at each occurrence, C1-C4 alkyl or benzyl.

[0194] In another embodiment of the compound of Formula (V), or a pharmaceutically acceptable salt thereof, R1 is C1-C3 alkyl, R2 is C1-C3 alkyl, R3 is a group R 3b and R 3b is independently at each occurrence C1-C6 alkyl-N(R5)2 or C1-C6 alkyl-(4- to 8-membered heterocycle), wherein each 4- to 8-membered heterocycle is optionally further substituted 1 to 4 times with C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or halo; R4 is hydrogen or methyl; R5 is independently at each occurrence C1-C4 alkyl or benzyl; However, when R1 is C2-C3 alkyl, R2 is C2-C3 alkyl, and R4 is methyl, R 3b is independently at each occurrence C1-C6 alkyl-N(R5)2 or C1-C6 alkyl-(4- to 8-membered heterocycle), wherein each 4- to 8-membered heterocycle is optionally further substituted once or twice with C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or halo.

[0195] In another embodiment of the compound of Formula (V), or a pharmaceutically acceptable salt thereof, R1 is C1-C3 alkyl, R2 is C1-C3 alkyl, R3 is a group R 3band R 3b is independently at each occurrence C1-C6 alkyl-N(R5)2 or C1-C6 alkyl-(4- to 8-membered heterocycle), wherein each 4- to 8-membered heterocycle is optionally further substituted 1 to 4 times with C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or halo; R4 is hydrogen or methyl; R5 is independently at each occurrence C1-C4 alkyl or benzyl; However, when R4 is methyl, R 3b is independently at each occurrence C1-C6 alkyl-N(R5)2 or C1-C6 alkyl-(4- to 8-membered heterocycle), wherein each 4- to 8-membered heterocycle is optionally further substituted once or twice with C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or halo.

[0196] Exemplary compounds of formula (V) include the following compounds, or pharmaceutically acceptable salts thereof: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0197] In certain embodiments, the compound of Formula (V) is one of the following compounds, or a pharmaceutically acceptable salt thereof: [ka] [ka] [ka]

[0198] In one embodiment, the compound of Formula (V) has the structure of compound 25: [ka]

[0199] In certain embodiments, the compound of Formula (V) has the structure of compound 32: [ka]

[0200] In one embodiment, the compound of Formula (V) has the structure of compound 34: [ka]

[0201] In certain embodiments, the compound of Formula (V) has the structure of compound 35: [ka]

[0202] In certain embodiments, the compound of Formula (V) has the structure of compound 37: [ka]

[0203] In one embodiment, the compound of Formula (V) has the structure of compound 80: [ka]

[0204] In one embodiment, the compound of Formula (V) has the structure of compound 81: [ka]

[0205] In one embodiment, the compound of Formula (V) has the structure of compound 82: [ka]

[0206] In one embodiment, the compound of Formula (V) has the structure of compound 84: [ka]

[0207] In one embodiment, the compound of Formula (V) has the structure of compound 85: [ka]

[0208] In one embodiment, the compound of Formula (V) has the structure of compound 86: [ka]

[0209] In one embodiment, the compound of Formula (V) has the structure of compound 87: [ka]

[0210] In one embodiment, the compound of Formula (V) has the structure of compound 88: [ka]

[0211] In one embodiment, the compound of Formula (V) has the structure of compound 90: [ka]

[0212] In one embodiment, the compound of Formula (V) has the structure of compound 94: [ka]

[0213] In one embodiment, the compound of Formula (V) has the structure of compound 95: [ka]

[0214] In one embodiment, the compound of Formula (V) has the structure of compound 96: [ka]

[0215] In one embodiment, the compound of Formula (V) has the structure of compound 98: [ka]

[0216] In one embodiment, the compound of Formula (V) has the structure of compound 100: [ka]

[0217] In one embodiment, the compound of Formula (V) has the structure of compound 105: [ka]

[0218] In one embodiment, the compound of Formula (V) has the structure of compound 106: [ka]

[0219] In one embodiment, the compound of Formula (V) has the structure of compound 120: [ka]

[0220] In certain embodiments, the compound of Formula (V) has the structure of compound 123: [ka]

[0221] Another aspect of the present disclosure is a compound selected from the group consisting of the compounds set forth below, or a pharmaceutically acceptable salt thereof: [ka]

[0222] In one embodiment, the disclosure provides a compound having the structure of compound 54: [ka]

[0223] In another aspect, the disclosure provides a compound having the structure of compound 20: [ka]

[0224] A further aspect of the present disclosure is a compound selected from the group consisting of the compounds set forth below, or a pharmaceutically acceptable salt thereof: [ka]

[0225] A further aspect of the present disclosure is a compound selected from the group consisting of the compounds set forth below, or a pharmaceutically acceptable salt thereof: [ka]

[0226] Synthetic Intermediates In another aspect, the present disclosure also relates to synthetic intermediates of the copper complexes described herein. In some embodiments, the synthetic intermediates have the formula (IA): [ka] wherein the variables L, R1, R2, R3, and R4 correspond to the variables of the same name as defined in formula (I).

[0227] Exemplary synthetic intermediates represented by formula (IA) include: [ka] [ka] [ka]

[0228] In some embodiments, the synthetic intermediate has formula (II-A): [ka] wherein the variables R1, R2, R3, and R4 correspond to the variables of the same name as defined in formula (II).

[0229] Exemplary synthetic intermediates represented by formula (II-A) include: [ka] [ka] [ka]

[0230] In some embodiments, the synthetic intermediate has formula (III-A): [ka] wherein the variables L, R1, R2, and R3 correspond to the variables of the same name as defined in formula (III).

[0231] Exemplary synthetic intermediates represented by formula (III-A) include: [ka]

[0232] In another aspect, the present disclosure also relates to synthetic intermediates of the copper complexes described herein. In some embodiments, the synthetic intermediates have the formula (IV-A): [ka] wherein the variables L, R1, R2, R3, and R4 correspond to the variables of the same name as defined in formula (IV).

[0233] Exemplary synthetic intermediates represented by formula (IV-A) include: [ka] [ka]

[0234] In some embodiments, the synthetic intermediate has the formula (VA): [ka] wherein the variables R1, R2, R3, and R4 correspond to the variables of the same name as defined in formula (V).

[0235] Exemplary synthetic intermediates represented by formula (VA) include: [ka] [ka] [ka] [ka] [ka]

[0236] Further exemplary synthetic intermediates of the present disclosure include the following compounds: [ka]

[0237] Pharmaceutical Composition In another aspect, provided herein is a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0238] The formulation of therapeutic compositions and their subsequent administration (dosing) are within the skill of those in the art. Dosing depends on the severity and responsiveness of the disease state being treated, with courses of treatment lasting from several days to several months, or until a sufficient diminution of the disease state is achieved. Optimal dosing schedules can be calculated from measurements of drug accumulation in the patient's body.

[0239] Those skilled in the art can readily determine optimal dosages, dosing techniques, and repetition rates. Optimal dosages may vary depending on the relative potency of the compounds of the present disclosure, and generally follow EC50 / ... 50 The dosage can be estimated based on the values. Generally, dosages are 0.01 μg to 100 g / kg body weight and may be given daily, weekly, monthly, or once or more per year, or even once every 2 to 20 years. Those skilled in the art can readily estimate the repetition rate of dosing based on the measured residence time and concentration of the drug in bodily fluids or tissues. After successful treatment, it may be desirable to subject the patient to maintenance therapy to prevent recurrence of the disease state, in which case the compounds of the present disclosure are administered at a maintenance dose ranging from 0.01 μg to 100 g / kg body weight once or more per day to once every 20 years.

[0240] Different dosing regimens may be used to treat neurodegenerative diseases (e.g., ALS). In some embodiments, a daily dosage, such as any of the exemplary dosages described above, is administered once, twice, three times, three times, or four times daily for 3, 4, 5, 6, 7, 8, 9, or 10 days. Depending on the stage and severity of the disease being treated, shorter treatment times (e.g., up to 5 days) may be used with higher doses, or longer treatment times (e.g., 10 days or more, or weeks, or a month, or longer) may be used with lower doses. In some embodiments, a once-daily or twice-daily dosage is administered every other day.

[0241] In some embodiments, the compounds of the present disclosure may be administered alone or in combination with at least one pharmaceutically acceptable excipient. The term "pharmaceutically acceptable" means acceptable for use in the pharmaceutical and veterinary fields, i.e., not unacceptably toxic or otherwise unsuitable. Examples of pharmaceutically acceptable adjuvants, diluents, excipients, etc. can be found in "Remington's: The Science and Practice of Pharmacy," 21st Ed., Lippincott Williams and Wilkins, 2005, the contents of which are incorporated herein by reference.

[0242] The compounds of the present disclosure can be administered in pure form or in suitable pharmaceutical compositions through any of the accepted administration modes or agents known in the art.The compounds of the present disclosure can be administered, for example, orally, nasally, parenterally (intravenously, intramuscularly, or subcutaneously), topically, transdermally, intravaginally, intravesically, intracisternally, or rectally.Dosage forms can be, for example, solid, semisolid, lyophilized powder, or liquid dosage forms, such as tablets, pills, soft elastic capsules or hard gelatin capsules, powders, solutions, suspensions, suppositories, aerosols, etc., in unit dosage forms suitable for easy administration of precise dosages. Some examples of suitable pharmaceutical carriers, including pharmaceutical diluents, are gelatin capsules; sugars such as lactose and sucrose; starches such as corn starch and potato starch, cellulose derivatives such as sodium carboxymethylcellulose, ethylcellulose, methylcellulose and cellulose acetate phthalate; gelatin; talc; stearic acid; magnesium stearate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and theobroma oil; propylene glycol, glycerin; sorbitol; polyethylene glycol; water; agar; alginic acid; isotonic saline and phosphate buffer; and other compatible substances that are commonly used in pharmaceutical preparations.Particular route of administration is oral, and can adjust convenient daily dosage regimen according to the severity of the disease to be treated.

[0243] Auxiliaries and adjuvants may include, for example, preservatives, wetting agents, suspending agents, sweeteners, flavorings, perfuming agents, emulsifying agents, and dispensing agents. Emulsifying agents may include polysorbates such as TWEEN, e.g., TWEEN-20 and TWEEN-80. Prevention of microbial action is generally provided by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. Isotonic agents, such as sugars and sodium chloride, may also be included. Prolonged absorption of injectable pharmaceutical forms can be achieved by the use of agents delaying absorption, for example, aluminum monostearate and gelatin. Auxiliaries may also include wetting agents, emulsifying agents, pH buffering agents, and antioxidants, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, and the like.

[0244] Solid dosage forms can be prepared with coatings and shells, such as enteric coatings and others known in the art. They can contain pacifying agents and can be of a composition that releases the compounds of the present disclosure in a delayed manner in a certain part of the intestinal tract. Examples of embedding compositions that can be used are polymeric substances and waxes. The compounds of the present disclosure can also be in microencapsulated form, if appropriate, containing one or more of the above-mentioned excipients.

[0245] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for example, by dissolving or dispersing the compounds of the present disclosure and optional pharmaceutical adjuvants in a carrier such as water, saline, aqueous dextrose, glycerol, ethanol, etc.; solubilizers and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan; or mixtures of these substances to form a solution or suspension.

[0246] Generally, depending on the intended mode of administration, a pharmaceutically acceptable composition will contain from about 1% to 99% by weight of a compound disclosed herein and from 99% to 1% by weight of a pharmaceutically acceptable excipient. In one example, the composition will be from about 5% to about 75% by weight of a compound disclosed herein, with the remainder being suitable pharmaceutical excipients.

[0247] Actual methods for preparing such dosage forms are known, or will be apparent, to those skilled in the art. See, for example, Remington's Pharmaceutical Sciences, 18th Ed. (Mack Publishing Company, Easton, Pa., 1990).

[0248] Treatment method The methods described herein include administering a therapeutically effective amount of a compound disclosed herein to a subject in need thereof. A "therapeutically effective amount" is an amount of a compound of the present disclosure that, when administered alone to a patient, effectively treats a neurodegenerative disease. An amount that is found to be a "therapeutically effective amount" for a particular subject in a given case may not be effective in 100% of subjects similarly treated for the disease or condition under consideration, even if such a dosage is considered a "therapeutically effective amount" by a medical professional. The amount of a compound of the present disclosure that corresponds to a therapeutically effective amount depends largely on the type of disease, the stage of the disease, the age of the patient being treated, and other factors.

[0249] Thus, in one aspect, the present disclosure provides a method for treating or preventing a neurodegenerative disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure. In particular, the method comprises administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), or (V). Non-limiting examples of neurodegenerative diseases that can be treated or prevented with the compounds disclosed herein include amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Parkinson's disease, Huntington's disease, and Alzheimer's disease. In a preferred embodiment, the neurodegenerative disease treated or prevented by the compounds of the present disclosure is ALS. In one embodiment, the ALS is familial ALS. In one embodiment, the ALS is sporadic ALS.

[0250] The amount of the compounds disclosed herein should provide effective treatment or prevention of neurodegenerative diseases, but preferably is not excessively toxic to the patient (i.e., the amount is preferably within toxicity limits as established by medical guidelines). In some embodiments, limits on the total dosage are imposed to prevent excessive toxicity of neurodegenerative diseases, or to provide more effective treatment, or both. Typically, the amounts contemplated herein are daily, although half-day and two- or three-day cycles are also contemplated herein.

[0251] In certain embodiments, a subject in need thereof is treatment naive. In certain embodiments, a subject in need thereof has received previous treatment for ALS, where the previous treatment was other than administration of a compound of the present disclosure, and the previous treatment was insufficient (e.g., as assessed by the subject and / or a physician), ineffective, and / or did not result in a detectable improvement in one or more parameters or symptoms associated with ALS and / or did not cause a biological effect correlated with the underlying pathology that caused the symptoms of ALS.

[0252] In certain embodiments, the subject in need is a human, and the human has a genetic mutation associated with ALS. In further embodiments, the genetic mutation associated with ALS comprises a mutation in the SOD1 gene.

[0253] In certain embodiments, the compounds of the present disclosure are administered to a subject in combination with additional ALS treatment therapies. Current treatments for ALS include the administration of riluzole and edaravone, which have been shown to be moderately effective. Other therapies for ALS include medications to treat specific symptoms associated with the disease. For example, muscle relaxants such as baclofen or diazepam may be prescribed to treat cramps, spasms, and spasticity. Gabapentin may be prescribed to help control pain. Medications such as amitriptyline, trihexyphenidyl, scopaderm, and glycopyrrolate may be administered to treat excessive saliva in the mouth due to difficulty swallowing. Medications may also be required to treat constipation, fatigue, depression, sleep difficulties, and emotional dysregulation associated with ALS.

[0254] In certain embodiments, compounds of the present disclosure may be administered to a subject to achieve a plasma C of about 50-650 ng / mL. max It is administered at a dose that achieves "C max The term "maximum concentration of active compound achieved in the plasma or spinal cord after administration of a drug" is defined as the maximum concentration of active compound achieved in the plasma or spinal cord after administration of a drug.

[0255] In another aspect, the present disclosure provides a method of treating, preventing, or diagnosing cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure. In particular, isotopes of the compounds disclosed herein (e.g., 64 Cu) may be used. Accordingly, in another aspect, the present disclosure provides a method of performing positron emission tomography (PET) imaging of a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the present disclosure, and then performing a PET scan on the subject.

[0256] In yet another aspect, the present disclosure provides a method of treating or preventing an infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0257] In a further aspect, the present disclosure provides a method for treating a disease or disorder associated with copper metabolism dysregulation (e.g., Menkes disease or Wilson disease) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure. In some embodiments, the subject has a congenital SOD1 deficiency or mutation. In some embodiments, the subject does not have a congenital SOD1 deficiency or mutation.

[0258] Preparation method Certain aspects of the present disclosure relate to processes for the preparation of compounds of Formula (I) described herein, or pharmaceutically acceptable salts thereof.

[0259] In certain embodiments, the process comprises reacting a compound of formula (IA): [ka] with a copper(II) salt to form a compound of formula (I), or a pharmaceutically acceptable salt thereof; During the ceremony, L is C3-C7 cycloalkyl, C1-C6 alkyl, or absent; R1 is a 5- to 10-membered heteroaryl, C1-C6 alkyl optionally substituted with NH2, NH(C1-C6 alkyl), or N(C1-C6 alkyl)2; R2 is a 5- to 10-membered heteroaryl, C1-C6 alkyl optionally substituted with NH2, NH(C1-C6 alkyl), or N(C1-C6 alkyl)2; R3 is C6~C 10 aryl, 5- to 10-membered heteroaryl, C(O)NH—(C1-C6 alkyl)-PPh3, hydroxy, C1-C6 alkoxy, or O—(C1-C6 alkyl)-O—(C1-C6 alkyl), where C6-C 10 The aryl is a group R 3a and the 5-10 membered heteroaryl is optionally substituted with a group R 3b is substituted once, twice, or three times with R 3a is independently at each occurrence a C3-C7 cycloalkyl or a 4- to 8-membered heterocycle, wherein the 4- to 8-membered heterocycle is optionally further substituted once, twice, or three times with a C1-C3 alkyl; R 3b is independently at each occurrence C1-C3 alkoxy, C3-C7 cycloalkyl, or a 4- to 8-membered heterocycle, wherein the heterocycle is optionally further substituted once, twice, or three times with C1-C3 alkyl; R4 is hydrogen, C1-C3 alkyl, or C6-C 10 Although it is aryl, provided that when L is absent, R3 is a group R 3a C6-C substituted once, twice, or three times 10 aryl, or when L is absent, R3 is a group R 3b provided that the heteroaryl is a 6- to 10-membered heteroaryl substituted once, twice, or three times with

[0260] In certain embodiments, the copper(II) salt is CuCl or Cu(OAc), or a hydrate thereof.

[0261] Another aspect of the present disclosure relates to processes for the preparation of compounds of formula (II) described herein, or pharmaceutically acceptable salts thereof.

[0262] In certain embodiments, the process comprises preparing a compound of formula (II-A): [ka] with a copper(II) salt to form a compound of formula (II), During the ceremony, R1 is a 5- to 10-membered heteroaryl, C1-C6 alkyl optionally substituted with NH2, NH(C1-C6 alkyl), or N(C1-C6 alkyl)2; R2 is a 5- to 10-membered heteroaryl, C1-C6 alkyl optionally substituted with NH2, NH(C1-C6 alkyl), or N(C1-C6 alkyl)2; R3 is a 4- to 8-membered heterocycle or a 5-membered heteroaryl, wherein the 4- to 8-membered heterocycle optionally contains a group R 3a and the 5-membered heteroaryl is optionally substituted with a group R 3b is substituted once, twice, or three times with R 3a independently at each occurrence, C1-C6 alkyl, C1-C6 alkyl-(C6-C 10 aryl), S(O)2H, S(O)2-(C1-C6 alkyl), S(O)2-(C3-C7 cycloalkyl), or S(O)2-(C6-C 10 aryl), R 3b is independently at each occurrence C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, halo, nitro, cyano, C(O)-(4- to 8-membered heterocycle), or C1-C6 alkyl-(4- to 8-membered heterocycle), wherein each 4- to 8-membered heterocycle is optionally further substituted once, twice, or three times with C1-C3 alkyl; R4 is hydrogen or C 1-3 It is alkyl.

[0263] In certain embodiments, the copper(II) salt is CuCl or Cu(OAc), or a hydrate thereof.

[0264] In another embodiment, the process comprises combining a compound of formula (II-A) with a zinc salt to produce a compound of formula (II-B): [ka] and mixing the compound of formula (II-B) with a copper(II) salt to form a compound of formula (II).

[0265] In certain embodiments, the zinc salt is Zn(OAc) 2 or a hydrate thereof.

[0266] In certain embodiments, the copper(II) salt is CuCl or Cu(OAc), or a hydrate thereof.

[0267] Yet another aspect of the present disclosure relates to processes for the preparation of compounds of formula (III), as described herein, or pharmaceutically acceptable salts thereof.

[0268] In certain embodiments, the process comprises preparing a compound of formula (III-A): [ka] with a copper(II) salt to form a compound of formula (III), During the ceremony, L is C1-C6 alkyl or absent; R1 is a 5- to 10-membered heteroaryl, C1-C6 alkyl optionally substituted with NH2, NH(C1-C6 alkyl), or N(C1-C6 alkyl)2; R2 is a 5- to 10-membered heteroaryl, C1-C6 alkyl optionally substituted with NH2, NH(C1-C6 alkyl), or N(C1-C6 alkyl)2; R3 is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, halo, hydroxy, C(O)NH2, C(O)NH(C1-C6 alkyl), C(O)N(C1-C6 alkyl)2, or C(O)-(4- to 8-membered heterocycle), wherein C1-C6 alkyl and C1-C6 alkoxy are optionally C6-C 10 The C(O)-(4- to 8-membered heterocycle) is optionally substituted once, twice, or three times with C1-C3 alkyl.

[0269] In certain embodiments, the copper(II) salt is CuCl or Cu(OAc), or a hydrate thereof.

[0270] In another embodiment, the process comprises mixing a compound of formula (III-A) with a zinc salt to produce a compound of formula (III-B): [ka] and mixing the compound of formula (III-B) with a copper(II) salt to form a compound of formula (III).

[0271] In certain embodiments, the zinc salt is Zn(OAc) 2 or a hydrate thereof.

[0272] In certain embodiments, the copper(II) salt is CuCl or Cu(OAc), or a hydrate thereof.

[0273] Another aspect of the present disclosure relates to processes for the preparation of compounds of formula (IV) described herein, or pharmaceutically acceptable salts thereof.

[0274] In certain embodiments, the process comprises preparing a compound of formula (IV-A): [ka] with a copper(II) salt to form a compound of formula (IV), or a pharmaceutically acceptable salt thereof; wherein the variables L, R1, R2, R3, and R4 correspond to the variables of the same name as defined in formula (IV).

[0275] In certain embodiments, the copper(II) salt is CuCl or Cu(OAc), or a hydrate thereof.

[0276] Yet another aspect of the present disclosure relates to a process for the preparation of a compound of formula (V), as described herein, or a pharmaceutically acceptable salt thereof.

[0277] In certain embodiments, the process comprises preparing a compound of formula (VA): [ka] with a copper(II) salt to form a compound of formula (V), or a pharmaceutically acceptable salt thereof; wherein the variables R1, R2, R3, and R4 correspond to the variables of the same name as defined in formula (V).

[0278] In certain embodiments, the copper(II) salt is CuCl or Cu(OAc), or a hydrate thereof.

[0279] In another embodiment, the process comprises mixing a compound of formula (VA) with a zinc salt to produce a compound of formula (VB): [ka] and mixing the compound of formula (VB) with a copper (II) salt to form a compound of formula (V).

[0280] In certain embodiments, the zinc salt is Zn(OAc) 2 or a hydrate thereof.

[0281] In certain embodiments, the copper(II) salt is CuCl or Cu(OAc), or a hydrate thereof. [Example]

[0282] The present disclosure further relates to the following examples. These examples are included merely to illustrate certain aspects and embodiments of the present disclosure and are not intended to limit the present disclosure. Thus, the present disclosure should in no way be construed as being limited to the following examples, but rather should be construed to encompass any and all variations that become evident as a result of the teachings provided herein.

[0283] Example 1: Preparation of Compounds 1-22 Scheme 1: Synthesis of Compound 1 [ka] Synthesis of N-methoxy-N-methyl-2-(pyridin-4-yl)acetamide: [ka] To a stirred mixture of 4-pyridineacetic acid (4.2 g, 24.2 mmol), N,O-dimethylhydroxylamine (2.8 g, 29.1 mmol), HOBt (3.9 g, 29.1 mmol), and TEA (12 mL, 84.7 mmol) in DCM (100 mL) at 4 °C, EDCI (5.6 g, 29.1 mmol) was added. The reaction was stirred overnight at ambient temperature. The mixture was washed with water (100 mL) and brine (100 mL). The organic layer was dried over anhydrous NaSO, filtered, and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent 100% DCM to 5% MeOH). Yield 2.9 g (66%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.14 min). MS (ESI) m / z 232.3 [MH]+. 1H-NMR (400MHz, CDCl3): δ (ppm) 3.21 (s, 3H), 3.66 (s, 3H), 3.78 (s, 2H), 7.24 (d, 2H), 8.55 (d, 2H).

[0284] Synthesis of 3-ethoxy-1-(pyridin-4-yl)but-3-en-2-one: [ka] A solution of ethyl vinyl ether (3.1 g, 42.9 mmol) in tetrahydrofuran (100 ml) was cooled to -78 °C, and tert-butyllithium in pentane (1.7 M, 23.0 ml, 38.8 mmol) was added. The mixture was warmed to 0 °C over a 1-hour period, stirred for 45 minutes, and cooled to -30 °C. A solution of N-methoxy-N-methyl-2-(pyridin-4-yl)acetamide (0.7 g, 3.8 mmol) in tetrahydrofuran (20 mL) was added, and the reaction was stirred at 0 °C for 2 hours. The progress of the reaction was monitored by TLC. The mixture was poured into aqueous NH Cl (100 ml) and extracted with Et O (3 × 50 ml). The combined extracts were dried over Na SO , the solution was decanted, and the solvent was removed under reduced pressure. The title compound was used in the next step without further purification. Yield 0.2 g (27%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 0.72 min). MS (ESI) m / z 192.4 [M−H]+. 1 H-NMR (400MHz, CDCl3): δ (ppm) 1.40 (t, 3H), 3.83 (q, 2H), 3.99 (s, 2H), 4.41 (d, 1H), 5.25 (d, 1H), 7.18 (dd, 1H), 8.55 (dd, 1H), 8.54 (dd, 2H).

[0285] Synthesis of INT-1, ((2Z,2'E)-2,2'-(1-(pyridin-4-yl)butan-2,3-diylidene)bis(N-methylhydrazine-1-carbothioamide)): [ka] 3-Ethoxy-1-(pyridin-4-yl)but-3-en-2-one (0.2 g, 1.04 mmol) was dissolved in EtOH (5 mL), methyl thiosemicarbazide (0.22 g, 2.08 mmol) and 3 drops of H2SO4 were added, and the reaction mixture was stirred at reflux for 4 hours and at ambient temperature overnight. The reaction progress was monitored by TLC. The precipitate was filtered, washed with EtOH, Et2O, and dried. Yield: 0.21 g (60%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile with 0.1% TFA, gradient 5 to 87% in 3 minutes, retention time 0.98 minutes). MS (ESI) m / z 338.9 [MH]+. 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 2.28 (s, 3H), 2.98 (d, 3H), 3.02 (d, 3H), 4.76 (s, 2H), 7.72 (d, 2H), 8.36 (dd, 1H), 8.50 (dd, 1H), 8.78 (d, 2H), 10.35 (s, 1H), 10.85 (s, 1H).

[0286] Synthesis of INT-5, ((2Z,2'E)-2,2'-(5-(pyridin-4-yl)pentane-2,3-diylidene)bis(N-methylhydrazine-1-carbothioamide)): [ka] INT-5 was made using a procedure similar to that for preparing INT-1. Yield 1.54 g (85%). LCMS (C18 column 20 x 2 mm, 2.5 μm particle size, 100 A pore size, water-acetonitrile + 0.1% TFA, 3 min gradient from 5 to 87%, retention time 0.94 min). MS (ESI) m / z 352.5 [M−H]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 2.15 (s, 3H), 2.66 (t, 2H), 3.01 (d, 6H), 3.28 (t, 2H), 7.32 (d, 2H), 8.21 (dd, 1H), 8.33 (dd, 1H), 8.45 (d, 2H), 10.21 (s, 1H), 10.67 (s, 1H).

[0287] Synthesis of INT-6, ((2Z,2'E)-2,2'-(5-(pyridin-3-yl)pentane-2,3-diylidene)bis(N-methylhydrazine-1-carbothioamide)): [ka] INT-6 was made using a procedure similar to that for preparing INT-1. Yield: 0.42 g (49%). LCMS (C18 column 20 x 2 mm, 2.5 μm particle size, 100 A pore size, water-acetonitrile + 0.1% TFA, 3 min gradient from 5 to 87%, retention time 0.94 min). MS (ESI) m / z 352.4 [M−H]+.

[0288] Synthesis of INT-9, ((2E,2'E)-2,2'-(1-(pyridin-3-yl)butane-2,3-diylidene)bis(N-methylhydrazine-1-carbothioamide)): [ka] INT-9 was made using a procedure similar to that for preparing INT-1. Yield: 8.6 g (76%). LCMS (C18 column 20 x 2 mm, 2.5 μm particle size, 100 A pore size, water-acetonitrile + 0.1% TFA, 3 min gradient from 5 to 87%, retention time 0.91 min). MS (ESI) m / z 338.4 [M−H]+.

[0289] Synthesis of INT-10, ((2E,2'E)-2,2'-(1-(6-methoxypyridin-3-yl)propane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide)): [ka] INT-10 was made using a procedure similar to that for preparing INT-1. Yield: 1.2 g (46.2%). LCMS (C18 column 20 x 2 mm, 2.5 μm particle size, 100 A pore size, water-acetonitrile + 0.1% TFA, 5 to 87% gradient in 3 min, retention time 1.52 min, MS (ESI) m / z 382.0 [M-H]+). 1 H-NMR (400MHz, CDCl3): δ (ppm) 0.94 (t, 3H), 1.15 (t, 3H), 2.35 (s, 3H), 3.34 (q, 2H), 3.60 (q, 2H), 3.91 (s, 3H), 6.44 (d, 1H), 7.62 (d, 1H), 8.05 (s, 1H), 8.68 (br.s, 1H), 9.54 (s, 1H), 10.71 (s, 1H).

[0290] Synthesis of INT-11, ((2E,2'E)-2,2'-(1-(6-methoxypyridin-3-yl)propane-1,2-diylidene)bis(N-methylhydrazine-1-carbothioamide)): [ka] INT-11 was made using a procedure similar to that for preparing INT-1. Yield: 0.7 g (56.6%). LCMS (C18 column 20 x 2 mm, 2.5 μm particle size, 100 A pore size, water-acetonitrile + 0.1% TFA, 5 to 87% gradient in 3 min, retention time 1.41 min, MS (ESI) m / z 354.5 [M-H]+). 1 H-NMR (400MHz, CDCl3): δ (ppm) 2.36 (s, 3H), 2.87 (s, 3H), 3.03 (s, 3H), 3.92 (s, 3H), 6.95 (d, 1H), 7.15 (br.s, 1H), 7.61 (d, 1H), 8.04 (s, 1H), 8.62 (br.s, 1H), 9.54 (s, 1H), 10.56 (s, 1H).

[0291] Synthesis of Compound 1: [ka] CuCl2·2H2O (0.08 g, 0.48 mmol) was added to INT-1 (0.15 g, 0.44 mmol) in ethanol (6 mL). The mixture was stirred overnight at ambient temperature. The complex was isolated as a reddish-brown powder. After cooling, the formed precipitate was collected by filtration, washed with water (2 × 50 mL), ethanol (2 × 50 mL), and a large amount of diethyl ether (5 × 50 mL), and then dried under vacuum. Yield: 0.075 g (42%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.29). MS (ESI) m / z 399.1 [M−H]+.

[0292] Synthesis of compound 5: [ka] The title compound was prepared from INT-5 according to the method for preparing compound 1. The complex was isolated as a reddish-brown powder. After cooling, the formed precipitate was collected by filtration, washed with water (2 x 50 ml), ethanol (2 x 50 ml), and a large amount of diethyl ether (5 x 50 ml), and then dried under vacuum. Yield 0.5 g (78%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.26). MS (ESI) m / z 413.4 [M−H]+.

[0293] Synthesis of compound 6: [ka] The title compound was prepared from INT-6 according to the method for preparing compound 1. The complex was isolated as a reddish-brown powder. After cooling, the precipitate formed was collected by filtration, washed with water (2 x 50 ml), ethanol (2 x 50 ml), and a large amount of diethyl ether (5 x 50 ml), and then dried under vacuum. Yield: 0.18 g (95%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.25). MS (ESI) m / z 412.9 [M−H]+.

[0294] Synthesis of compound 9: [ka] The title compound was prepared from INT-9 according to the method for preparing compound 1. The complex was isolated as a reddish-brown powder. After cooling, the precipitate formed was collected by filtration, washed with water (2 x 50 ml), ethanol (2 x 50 ml), and a large amount of diethyl ether (5 x 50 ml), and then dried under vacuum. Yield 2.3 g (97%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.30). MS (ESI) m / z 399.1 [M−H]+.

[0295] Synthesis of compound 10: [ka] The title compound was prepared from INT-10 according to the method for preparing compound 1. The formed complex precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum. Yield 0.13 g (37.3%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 2.31). MS (ESI) m / z 443.5 [M−H]+.

[0296] Synthesis of compound 11: [ka] The title compound was prepared from INT-11 according to the method for preparing compound 1. The formed complex precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum. Yield 0.12 g (34.5%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.97). MS (ESI) m / z 415.3 [M−H]+.

[0297] Scheme 2: Synthesis of Compound 2 [ka] Synthesis of ethyl 2-(pyridin-3-yl)acetate: [ka] To a stirred solution of 3-pyridineacetic acid (25.0 g, 145 mmol) in EtOH (250 ml) at 0-5°C, SOCl2 (11.6 ml, 160 mmol) was added over a period of 15 minutes. The reaction was then heated to reflux for an additional 16 hours. EtOH was evaporated under reduced pressure. To the residue was added 2 M aqueous Na2CO3 (30 ml), and the resulting mixture was extracted with EtOAc (3 x 400 ml). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound as a colorless liquid. Yield 22.3 g (93%). 1 H-NMR (400MHz, CDCl3): δ (ppm): 1.26 (t, 3 H), 3.62 (s, 2 H), 4.17 (q, 2 H), 7.27-7.28 (m, 1 H), 7.64-7.65 (m, 1 H), 8.53 (m, 2 H).

[0298] Synthesis of ethyl 1-(pyridin-3-yl)cyclopentane-1-carboxylate: [ka] To a stirred suspension of sodium hydride (7.3 g, 181 mmol, 60% in oil) in anhydrous THF (160 ml) at 0 °C, a solution of ethyl 2-(pyridin-3-yl)acetate (10.0 g, 60.5 mmol) in anhydrous THF (35 ml) was added dropwise. The reaction mixture was stirred at 0 °C for 30 min (until gas formation ceased). Dibromobutane (19.6 g, 90.5 mmol) was then added at 0 °C, and the reaction mixture was stirred at ambient temperature for 14 h. The reaction mixture was then quenched with saturated aqueous ammonium chloride solution (60 ml). The reaction mixture was extracted with EtOAc (3 × 40 ml). The organic phase was washed with brine (100 ml), dried over anhydrous NaSO, filtered, and concentrated. The resulting dark solid was purified by flash chromatography (silica gel, eluted with hexane-ethyl acetate, 4:1 to 1:1). Yield: 9.8 g (74%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.01 min). MS (ESI) m / z 220.6 [M−H]+. 1 H-NMR (400MHz, CDCl3): δ (ppm) 1.16 (t, 3H), 1.74-1.78 (m, 4H), 1.88-1.98 (m, 2H), 2.67-2.73 (m, 2H), 4.09 (q, 2H), 7.23-7.27 (m, 1H), 7.67-7.71 (m, 1H), 8.49 (dd, 1H), 8.65 (dd, 1H).

[0299] Synthesis of 1-(pyridin-3-yl)cyclopentane-1-carboxylic acid: [ka] A solution of ethyl 1-(pyridin-3-yl)cyclopentane-1-carboxylate (8.4 g, 38.5 mmol) in MeOH (60 ml) was added to a 20% aqueous solution of LiOH (2.5 g, 96.2 mmol). The reaction mixture was stirred at 60 °C for 8 h. The solvent was then removed by lyophilization, and the corresponding crude product was used in the next step without further purification. Yield 7 g (80%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 0.82 min). MS (ESI) m / z 192.1 [M−H]+. 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 1.66-1.70 (m, 4H), 1.85-1.92 (m, 2H), 2.52-2.58 (m, 2H), 7.56 (dd, 1H), 7.98-8.02 (m, 1H), 8.58 (dd, 1H), 8.66 (d, 1H), 12.66 (br.s, 1H).

[0300] Synthesis of N-methoxy-N-methyl-1-(pyridin-3-yl)cyclopentane-1-carboxamide: [ka] To a stirred mixture of 1-(pyridin-3-yl)cyclopentane-1-carboxylic acid (5.0 g, 22.0 mmol), N,O-dimethylhydroxylamine (2.6 g, 26.4 mmol), HOBt (3.6 g, 26.4 mmol), and TEA (10.8 ml, 77 mmol) in DCM (150 ml) at 4 °C, EDCI (5.1 g, 26.4 mmol) was added. The reaction was stirred overnight at ambient temperature. The mixture was washed with water (100 ml) and brine (100 ml). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent 100% DCM to 5% MeOH) to give the title compound. Yield 2.5 g (49%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 0.84 min). MS (ESI) m / z 235.3 [MH]+. 1 H-NMR (400MHz, CDCl3): δ (ppm) 1.66-1.81 (m, 4H), 2.05-2.11 (m, 2H), 2.42-2.48 (m, 2H), 2.89 (s, 3H), 3.13 (s, 3H), 7.34 (q, 1H), 7.65 (d, 1H), 8.49 (d, 1H), 8.59 (d, 1H).

[0301] Synthesis of 2-ethoxy-1-(1-(pyridin-3-yl)cyclopentyl)prop-2-en-1-one: [ka] A solution of ethyl vinyl ether (1.69 g, 23.6 mmol) in tetrahydrofuran (40 ml) was cooled to −78° C., and tert-butyllithium in pentane (1.7 M, 13.0 ml, 21.5 mmol) was added. The mixture was warmed to 0° C. over a 1-hour period, stirred for 45 minutes, and cooled to −30° C. A solution of N-methoxy-N-methyl-1-(pyridin-3-yl)cyclopentane-1-carboxamide (1.0 g, 4.3 mmol) in THF (15 ml) was added, and the reaction was stirred at 0° C. for 4 hours. The progress of the reaction was monitored by TLC. The mixture was poured into aqueous NH4Cl (100 ml) and extracted with Et2O (3×50 ml). The combined extracts were dried over Na2SO4. The solution was decanted, and the solvent was removed under reduced pressure. The title compound was used without further purification. Yield 0.85 g (81%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.11 min). MS (ESI) m / z 246.4 [MH]+. 1 H-NMR (400MHz, CDCl3): δ (ppm) 1.05 (t, 3H), 1.69-1.73 (m, 4H), 2.06-2.08 (m, 2H), 2.46-2.52 (m, 2H), 3.50 (q, 2H),4.30 (d, 1H), 5.18 (d, 1H), 7.21-7.25 (m, 1H), 7.51-7.54 (m, 1H), 8.45 (dd, 1H), 8.52 (d, 1H).

[0302] Synthesis of INT-2, ((2Z,2'E)-2,2'-(1-(1-(pyridin-3-yl)cyclopentyl)propane-1,2-diylidene)bis(N-methylhydrazine-1-carbothioamide)): [ka] 2-Ethoxy-1-(1-(pyridin-3-yl)cyclopentyl)prop-2-en-1-one (0.85 g, 3.5 mmol) was dissolved in EtOH (5 mL), methyl thiosemicarbazide (0.80 g, 7.7 mmol) and 3 drops of H2SO4 were added, and the reaction mixture was stirred at reflux for 4 hours and at ambient temperature overnight. The reaction progress was monitored by TLC. The precipitate was filtered, washed with EtOH, Et2O, and dried. Yield 0.21 g (15%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 minutes, retention time 1.00 minutes). MS (ESI) m / z 392.3 [MH]+.

[0303] Synthesis of INT-3, ((2Z,2'E)-2,2'-(1-(1-(pyridin-3-yl)cyclobutyl)propane-1,2-diylidene)bis(N-methylhydrazine-1-carbothioamide)): [ka] INT-3 was made using a procedure similar to that for preparing INT-2. Yield 0.08 g (10%). LCMS (C18 column 20 x 2 mm, 2.5 μm particle size, 100 A pore size, water-acetonitrile + 0.1% TFA, 5 to 87% gradient in 3 min, retention time 1.01 min). MS (ESI) m / z 378.5 [M−H]+.

[0304] Synthesis of INT-4, ((2Z,2'E)-2,2'-(4-(pyridin-3-yl)pentane-2,3-diylidene)bis(N-methylhydrazine-1-carbothioamide)): [ka] INT-4 was made using a procedure similar to that for preparing INT-2. Yield: 0.58 g (42%). LCMS (C18 column 20 x 2 mm, 2.5 μm particle size, 100 A pore size, water-acetonitrile + 0.1% TFA, 3 min gradient from 5 to 87%, retention time 0.96 min). MS (ESI) m / z 352.3 [M−H]+.1 H-NMR (400MHz, DMSO-d6): δ (ppm) 1.52 (d, 3H), 2.24 (s, 3H), 2.90 (d, 3H), 3.00 (d, 3H), 5.23 (q, 1H), 7.32-7.34 (m, 1H), 7.39-7.42 (m, 1H), 7.62 (d, 1H), 8.40 (s, 1H), 8.46 (d, 2H), 9.84 (s, 1H), 10.30 (s, 1H).

[0305] Synthesis of compound 2: [ka] CuCl2·2H2O (0.08 g, 0.5 mmol) was added to INT-2 (0.18 g, 0.46 mmol) in ethanol (6 mL). The mixture was stirred overnight at ambient temperature. The complex was isolated as a reddish-brown powder. After cooling, the formed precipitate was collected by filtration, washed with water (2 × 50 mL), ethanol (2 × 50 mL), and a large amount of diethyl ether (5 × 50 mL), and then dried under vacuum. Yield: 0.08 g (39%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 2.01). MS (ESI) m / z 453.4 [M−H]+.

[0306] Synthesis of compound 3: [ka] The title compound was prepared from INT-3 according to the method for preparing compound 2. The complex formed was isolated as a reddish-brown powder. After cooling, the precipitate formed was collected by filtration, washed with water (2 x 50 ml), ethanol (2 x 50 ml), and a large amount of diethyl ether (5 x 50 ml), and then dried under vacuum. Yield: 0.05 g (61%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.49). MS (ESI) m / z 439.0 [M−H]+.

[0307] Synthesis of compound 4: [ka] The title compound was prepared from INT-4 according to the method for preparing compound 2. The complex was isolated as a reddish-brown powder. After cooling, the precipitate formed was collected by filtration, washed with water (2 x 50 ml), ethanol (2 x 50 ml), and a large amount of diethyl ether (5 x 50 ml), and then dried under vacuum. Yield: 0.61 g (89%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.30). MS (ESI) m / z 413.5 [M−H]+.

[0308] Scheme 3: Synthesis of Compound 7 [ka] Synthesis of 2-(6-morpholinopyridin-3-yl)acetonitrile: [ka] A solution of (6-chloropyridin-3-yl)acetonitrile (1.8 g, 11.8 mmol), triethylamine (3.3 mL, 23.5 mmol), and morpholine (1.13 g, 13.1 mmol) in n-butanol (15 mL) was heated at 150 °C for 2 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, CCl4-ethyl acetate 8:2). Yield 0.7 g (29%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 0.91 min). MS (ESI) m / z 204.1 [M−H]+. 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 2.42 (d, 4H), 3.69 (d, 4H), 3.86-3.88 (m, 2H), 6.83-6.87 (m, 1H), 7.52-7.55 (m, 1H), 8.08 (s, 1H).

[0309] Synthesis of 2-(6-morpholinopyridin-3-yl)acetic acid: [ka] A mixture of 2-(6-morpholinopyridin-3-yl)acetonitrile (1.0 g, 5.2 mmol) in concentrated hydrochloric acid (15 mL) was refluxed for 3 hours. The liquid was evaporated in vacuo to give the crude product as a white solid (1.40 g, 86.8%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 minutes, retention time 0.51 minutes). MS (ESI) m / z 223.6 [MH]+. 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 3.66 (s, 2H), 3.73 (s, 8H), 7.36 (d, 1H), 7.94 (dd, 1H), 7.97 (d, 1H), 13.94 (br.s, 1H).

[0310] Synthesis of N-methoxy-N-methyl-2-(6-morpholinopyridin-3-yl)acetamide: [ka] To a mixture of 2-(6-morpholinopyridin-3-yl)acetic acid (1.4 g, 4.5 mmol), N,O-dimethylhydroxylamine (0.53 g, 5.4 mmol), HOBt (0.73 g, 5.4 mmol), and TEA (2.2 mL, 15.7 mmol) in DCM (25 mL) at 4 °C, EDCI (1.03 g, 5.4 mmol) was added. The reaction was stirred overnight at ambient temperature. The mixture was washed with water (100 mL) and brine (100 mL). The organic layer was dried over anhydrous NaSO, filtered, and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent 100% DCM to 5% MeOH) to give the crude title product. Yield 1.0 g (84%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 0.91 min). MS (ESI) m / z 266.5 [M−H]+. 1 H-NMR (400MHz, CDCl3): δ (ppm) 3.20 (s, 3H), 3.48 (t, 4H), 3.65 (s, 2H), 3.68 (s, 3H),3.82 (t, 4H), 6.63 (d, 1H), 7.52 (dd, 1H), 8.09 (d, 1H).

[0311] Synthesis of 3-ethoxy-1-(6-morpholinopyridin-3-yl)but-3-en-2-one: [ka] A solution of ethyl vinyl ether (3.0 g, 41.8 mmol) in tetrahydrofuran (50 mL) was cooled to −78° C., and tert-butyllithium in pentane (1.7 M, 20.2 mL, 34.6 mmol) was added. The mixture was warmed to 0° C. over a 1-hour period, stirred for 45 minutes, cooled to −30° C., and magnesium bromide etherate (8.9 g, 34.6 mmol) was added. The mixture was warmed to 0° C. over a 15-minute period, and a solution of N-methoxy-N-methyl-2-(6-morpholinopyridin-3-yl)acetamide (1.0 g, 3.8 mmol) in tetrahydrofuran (20 mL) was added. The mixture was allowed to reach room temperature and stirred overnight. The progress of the reaction was monitored by TLC. The mixture was poured into aqueous NH4Cl (100 mL) and extracted with Et2O (3 × 50 mL). The combined extracts were dried over Na2SO4. The solution was decanted and the solvent removed under reduced pressure. The title compound was used in the next step without further purification. Yield 0.26 g (25%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 0.96 min). MS (ESI) m / z 277.5 [M−H]+. 1 H-NMR (400MHz, CDCl3): δ (ppm) 1.43 (t, 3H), 2.01-2.04 (m, 4H), 3.46-3.51 (m, 4H), 3.82 (q, 2H), 3.84 (s, 2H), 4.41 (d, 1H), 5.22 (d, 1H), 6.39 (dd, 1H), 7.38 (dd, 1H), 8.01 (dd, 1H).

[0312] Synthesis of INT-7, ((2E,2'E)-2,2'-(1-(6-morpholinopyridin-3-yl)butane-2,3-diylidene)bis(N-ethylhydrazine-1-carbothioamide)): [ka] 3-Ethoxy-1-(6-morpholinopyridin-3-yl)but-3-en-2-one (0.26 g, 0.94 mmol) was dissolved in EtOH (5 mL), ethyl thiosemicarbazide (0.22 g, 1.88 mmol) and 3 drops of H2SO4 were added, and the reaction mixture was stirred at reflux for 4 hours and at ambient temperature overnight. The reaction progress was monitored by TLC. The precipitate was filtered, washed with EtOH, Et2O, and dried. Yield: 0.41 g (97%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile with 0.1% TFA, gradient 5 to 87% in 3 minutes, retention time 1.14 minutes). MS (ESI) m / z 451.5 [M−H]+.

[0313] Synthesis of INT-8, ((2E,2'E)-2,2'-(1-(6-(pyrrolidin-1-yl)pyridin-3-yl)butane-2,3-diylidene)bis(N-ethylhydrazine-1-carbothioamide)): [ka] INT-8 was made using a procedure similar to that for preparing INT-7. Yield 0.25 g (99%). LCMS (C18 column 20 x 2 mm, 2.5 μm particle size, 100 A pore size, water-acetonitrile + 0.1% TFA, 3 min gradient from 5 to 87%, retention time 1.17 min). MS (ESI) m / z 435.5 [M−H]+.

[0314] Synthesis of compound 7: [ka] CuCl2·2H2O (0.07 g, 0.4 mmol) was added to INT-7 (0.18 g, 0.4 mmol) in ethanol (6 mL). The mixture was stirred overnight at ambient temperature. The complex was isolated as a reddish-brown powder. After cooling, the formed precipitate was collected by filtration, washed with water (2 × 50 mL), ethanol (2 × 50 mL), and copious amounts of diethyl ether (5 × 50 mL), and then dried under vacuum. Yield: 0.03 g (14%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.55). MS (ESI) m / z 512.7 [M−H]+.

[0315] Synthesis of compound 8: [ka] The title compound was prepared from INT-8 according to the method for preparing compound 7. The complex was isolated as a reddish-brown powder. After cooling, the formed precipitate was collected by filtration, washed with water (2 x 50 ml), ethanol (2 x 50 ml), and a large amount of diethyl ether (5 x 50 ml), and then dried under vacuum. Yield 0.05 g (16%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.57). MS (ESI) m / z 496.5 [M−H]+.

[0316] Scheme 4: Synthesis of compound 12 [ka] Synthesis of 1-(4-acetylphenyl)pyrrolidin-2-one: [ka] To a mixture of pyrrolidin-2-one (1.7 g, 20.0 mmol), 1-(4-iodophenyl)ethanone (4.1 g, 16.7 mmol), CuI (0.32 g, 1.67 mmol), and glycine (0.25 g, 3.34 mmol) was added potassium phosphate (2.1 g, 40.0 mmol). The glass tube was evacuated, backfilled with argon at room temperature, and sealed. DMF (0.5 mL) was added via syringe under argon. The mixture was then stirred at 100 °C for 24 h. The cooled mixture was partitioned between water and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluting with a gradient of 1:8 to 1:2 ethyl acetate-hexane) to provide the title compound. Yield: 3.2g (94%). 1 H-NMR (400MHz, CDCl3): δ (ppm) 2.22 (m, 2H), 2.60 (s, 3H), 2.66 (t, 2H), 3.92 (t, 2H), 7.77 (dd, 2H), 7.99 (dd, 2H).

[0317] Synthesis of 2-oxo-2-(4-(2-oxopyrrolidin-1-yl)phenyl)acetaldehyde: [ka] A flask was charged with SeO2 (0.16 g, 1.5 mmol), 1,4-dioxane (3 mL), and water (0.5 mL). The mixture was heated to 50 °C and stirred until most of the SeO2 was dissolved. 1-(4-Acetylphenyl)pyrrolidin-2-one (0.3 g, 1.47 mmol) was added, and the reaction was heated at gentle reflux overnight. The progress of the reaction was monitored by TLC (CCl4-EtOAc 7:3). Selenium solids precipitated over the course of the reaction. The mixture was cooled in an ice bath and filtered through diatomaceous earth to remove the selenium. The filter cake was washed with portions of 1,4-dioxane. The filtrate was concentrated in vacuo until most of the 1,4-dioxane was removed. The crude product was used in the next step without further purification. Yield 0.25 g (83%).

[0318] Synthesis of INT-12, (2Z,2'E)-2,2'-(1-(4-(2-oxopyrrolidin-1-yl)phenyl)ethane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide): [ka] 2-Oxo-2-(4-(2-oxopyrrolidin-1-yl)phenyl)acetaldehyde (0.25 g, 1.2 mmol) was dissolved in EtOH (5 mL), ethyl thiosemicarbazide (0.35 g, 2.4 mmol) and 3 drops of H2SO4 were added, and the reaction mixture was stirred at reflux for 4 h and at ambient temperature for 15 h. The reaction progress was monitored by TLC (CCl4-EtOAc 7:3). The precipitate formed was filtered, washed with EtOH, water, Et2O, and dried. Yield 0.45 g (73%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile with 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.49 min). MS (ESI) m / z 420.5 [M−H]+. 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 1.15 (t, 3H), 1.19 (t, 3H), 2.94-2.11 (m, 2H), 2.28 (s, 1H0, 3.36-3.47 (m, 1H), 3.57-3.65 (m, 4H), 3.82 (t, 2H), 7.69-7.82 (m, 4H), 7.94 (d, 1H), 8.23 ​​(s, 1H), 8.91 (t, 1H), 11.77 (s, 1H), 12.31 (s, 1H).

[0319] Synthesis of INT-14, ((2Z,2'E)-2,2'-(1-(4-(pyrrolidin-1-yl)phenyl)ethane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide)) [ka] INT-14 was made using a procedure similar to that for preparing INT-12. Yield: 0.3 g (15.5%). LCMS (C18 column 20 x 2 mm, 2.5 μm particle size, 100 A pore size, water-acetonitrile + 0.1% TFA, 5 to 87% gradient in 3 min, retention time 1.92 min, MS (ESI) m / z 406.3 [M-H]+). 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 1.12-1.24 (m, 6H), 1.91-2.06 (m, 4H), 3.19-3.29 (m,4H), 3.53-3.66 (m, 4H), 6.58 (d, 2H), 7.65 (d, 2H), 7.93 (br.s, 1H), 8.22 (s, 1H), 8.74 (br.s, 1H), 11.73 (s, 1H), 12.16 (s, 1H).

[0320] Synthesis of INT-15, ((2Z,2'E)-2,2'-(1-(4-morpholinophenyl)ethane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide)) [ka] INT-15 was made using a procedure similar to that for preparing INT-12. Yield 1.1 g (53.5%). LCMS (C18 column 20 x 2 mm, 2.5 μm particle size, 100 A pore size, water-acetonitrile + 0.1% TFA, 5 to 87% gradient in 3 min, retention time 1.66 min, MS (ESI) m / z 422.4 [M-H]+). 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 1.16 (t, 3H), 1.20 (t, 3H), 3.16-3.24 (m, 4H), 3.54-3.66 (m, 4H), 3.71-3.79 (m, 4H), 7.00 (d, 2H), 7.23 (br.s, 1H), 7.70 (d, 2H), 7.95 (br.s, 1H), 8.83 (br.s, 1H), 11.74 (s, 1H), 12.23 (s, 1H).

[0321] Synthesis of compound 12: [ka] CuCl2·2H2O (0.16 g, 0.9 mmol) was added to INT-12 (0.4 g, 0.9 mmol) in ethanol. The mixture was stirred at ambient temperature for 15 h. The formed complex precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum. Yield 0.016 g (4%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.84). MS (ESI) m / z 481.3 [M−H]+.

[0322] Synthesis of compound 14: [ka] The title compound was prepared from INT-14 according to the method for preparing compound 12. The complex formed precipitated as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum. Yield 0.057 g (49.6%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 2.34). MS (ESI) m / z 467.0 [M−H]+.

[0323] Synthesis of compound 15: [ka] The title compound was prepared from INT-15 according to the method for preparing compound 12. The complex formed precipitated as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum to give the title product. Yield 0.17 g (85%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.97). MS (ESI) m / z 483.5 [M−H]+.

[0324] Scheme 5: Synthesis of compound 13 [ka] Synthesis of 4-morpholinobenzonitrile: [ka] A stirred solution of 4-fluorobenzonitrile (2.0 g, 16.5 mmol) in anhydrous dimethylformamide (5 mL), morpholine (1.44 g, 16.5 mmol), and K2CO3 (2.85 g, 20.6 mmol) was added and heated at 110 °C for 18 h. Water was added, and the precipitate formed was filtered and washed with water and hexane. Yield 2.6 g (83%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.24 min). MS (ESI) m / z 189.1 [MH]+. 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 3.27 (t, 4H), 3.72 (t, 4H), 7.02 (d, 2H), 7.60 (d, 2H).

[0325] Synthesis of 4-morpholinobenzoic acid: [ka] A stirred solution of 4-morpholin-4-yl-benzonitrile (2.6 g, 14.7 mmol) and sodium hydroxide (2.2 g, 58.8 mmol) in a mixture of water (90 ml) and MeOH (5 ml) was heated to reflux on a water bath for 5 hours. The solution was then cooled to room temperature and acidified with aqueous HCl (10%). The precipitate was filtered, washed with water, dried under vacuum at 60 °C, and crystallized from EtOH to give compound 2. Yield 2.0 g (70%). 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 3.12 (t, 2H), 3.24 (t, 2H), 3.73 (t, 4H), 6.96 (t, 2H), 7.77 (t, 2H), 12.31 (br.s, 1H).

[0326] Synthesis of N-methoxy-N-methyl-4-morpholinobenzamide: [ka] To a mixture of 4-morpholinobenzoic acid (1.4 g, 6.7 mmol), N,O-dimethylhydroxylamine (1.3 g, 8.7 mmol), HOBT (1.0 g, 7.7 mmol), and TEA (0.9 mL, 9 mmol) in DCM (25 mL) at 4 °C was added EDCI (1.4 g, 9 mmol). The reaction was stirred overnight at ambient temperature. The mixture was washed with water (15 mL), 1N aqueous HCl (20 mL), water (50 mL), and brine (100 mL). The organic layer was dried over anhydrous NaSO, filtered, and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent 100% DCM to 5% MeOH) to give the crude title product. Yield 0.97 g (58%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.12 min). MS (ESI) m / z 251.6 [MH]+. 1H-NMR (400MHz, CDCl3): δ (ppm) 3.26 (t, 4H), 3.36 (s, 3H), 3.59 (s, 3H), 3.89 (t, 4H), 6.89 (d, 2H), 7.74 (d, 2H).

[0327] Synthesis of 2-ethoxy-1-(4-morpholinophenyl)prop-2-en-1-one: [ka] A solution of ethyl vinyl ether (0.9 g, 12.2 mmol) in anhydrous tetrahydrofuran (25 ml) was cooled to −78° C., and tert-butyllithium in pentane (1.7 M, 6.6 ml, 11.1 mmol) was added. The mixture was warmed to 0° C. over a 1-hour period, stirred for 45 minutes, and cooled to −30° C. A solution of N-methoxy-N-methyl-4-morpholinobenzamide (0.93 g, 3.7 mmol) in THF (10 ml) was then added, and the mixture was stirred at 0° C. for 4 hours. The progress of the reaction was monitored by TLC. The mixture was poured into aqueous NH4Cl (100 ml) and extracted with Et2O (3 × 100 ml). The combined extracts were dried over Na2SO4, filtered, and evaporated. The product was used in the next step without further purification. Yield 0.6 g (62%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.40 min). MS (ESI) m / z 262.0 [M−H]+. 1 H-NMR (400MHz, CDCl3): δ (ppm) 1.42 (t, 3H), 3.33 (t, 4H), 3.87 (t, 4H), 3.94 (q, 2H), 4.65 (d, 1H), 4.91 (d, 1H), 6.87 (d, 2H), 7.92 (d, 2H).

[0328] Synthesis of INT-13, ((2Z,2'E)-2,2'-(1-(4-morpholinophenyl)propane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide)): [ka] 2-Ethoxy-1-(4-morpholinophenyl)prop-2-en-1-one (0.6 g, 2.3 mmol) was dissolved in EtOH (5 mL), ethyl thiosemicarbazide (0.6 g, 5.1 mmol) and 3 drops of H2SO4 were added, and the reaction mixture was stirred at reflux for 4 h and at ambient temperature for 15 h. The precipitate formed was filtered, washed with EtOH, water, Et2O, and dried. Yield 0.3 g (30%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile with 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.49 min). MS (ESI) m / z 436.4 [M−H]+. 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 0.93 (t, 3H), 1.15 (t, 3H), 2.33 (s, 3H), 3.19 (t, 4H), 3.34-3.38 (m, 2H), 3.56-3.63 (m, 2H), 3.75 (t, 4H), 6.97 (t, 1H), 7.12 (q, 4H), 8.70 (s, 1H), 8.74 (t, 1H), 10.75 (s, 1H).

[0329] Synthesis of compound 13: [ka] CuCl22H2O (0.07 g, 0.4 mmol) was added to INT-13 (0.17 g, 0.4 mmol) in ethanol. The mixture was stirred at ambient temperature for 15 hours. The formed complex precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum. Yield 0.2 g (99%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 minutes, retention time 1.87). MS (ESI) m / z 497.4 [M−H]+.

[0330] Scheme 6: Synthesis of compound 16 [ka] Synthesis of 1-(4-morpholinophenyl)-2-phenylethane-1,2-dione: [ka] To a stirred solution of 4-morpholinobenzaldehyde (24.0 g, 125 mmol) and benzaldehyde (13.3 g, 125 mmol) in EtOH (50 mL) was added a solution of potassium cyanide (0.43 g, 66 mmol) in water (35 mL). The mixture was stirred at reflux for 5 h and cooled to ambient temperature. The solution was placed in a refrigerator at approximately 8 °C for fractional crystallization. The formed precipitate, consisting mainly of alpha-hydroxyketone, was removed by filtration and discarded, and the filtrate was evaporated to dryness in vacuo. The residue was purified by column chromatography (silica gel, eluent EtOAc-hexane). Yield 2.2 g (6%). 1 H-NMR (400MHz, CDCl3): δ (ppm) 3.36-3.40 (m, 4H), 3.84-3.89 (m, 4H), 6.87 (d, 2H), 7.50 (dd, 2H), 7.64 (dd, 1H), 7.88 (d, 2H), 7.99 (d, 2H).

[0331] Synthesis of INT-16, ((2E,2'E)-2,2'-(1-(4-morpholinophenyl)-2-phenylethane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide)): [ka] 1-(4-Morpholinophenyl)-2-phenylethane-1,2-dione (0.61 g, 2.06 mmol, 1 equiv.) was dissolved in EtOH (15 ml), methyl thiosemicarbazide (0.45 g, 2 equiv.) and 3 drops of H2SO4 were added, and the reaction mixture was stirred at reflux for 4 h and at ambient temperature for 15 h. The formed precipitate was filtered, washed with EtOH, water, Et2O, and dried. Yield 0.45 g (44%).1 H-NMR (400MHz, DMSO-d6): δ (ppm) 1.13-1.19 (m, 6H), 3.17-3.20 (m, 4H), 3.55 (q, 4H), 3.70-3.75 (m, 4H), 6.94 (d, 2H), 7.42-7.47 (m, 3H), 7.55 (d, 2H), 7.70-7.74 (m, 2H), 8.88 (ddd, 2H), 9.49 (d, 2H).

[0332] Synthesis of INT-17, ((2E,2'E)-2,2'-(1-(4-morpholinophenyl)-2-phenylethane-1,2-diylidene)bis(N-methylhydrazine-1-carbothioamide)): [ka] INT-17 was made using a procedure similar to that for preparing INT-16. Yield 0.31 g (36%). 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 2.99-3.06 (m, 6H), 3.17-3.20 (m, 4H), 3.70-3.74 (m, 4H), 6.94 (d, 2H), 7.42-7.47 (m, 3H), 7.55 (d, 2H), 7.70-7.74 (m, 2H), 8.84 (ddd, 2H), 9.49 (d, 2H).

[0333] Synthesis of compound 16: [ka] Cu(OAc)2H2O (0.06 g, 1.1 equiv.) was added to INT-16 (0.12 g, 0.26 mmol, 1 equiv.) in ethanol. The mixture was stirred at ambient temperature for 15 h. The formed complex precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum. Yield 0.03 g (22%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 2.21 min). MS (ESI) m / z 559.0 [M−H]+.

[0334] Synthesis of compound 17: [ka] The title compound was prepared from INT-17 according to the method for preparing compound 16. The formed complex precipitated from the reaction mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum. Yield 0.03 g (22%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 2.24 min). MS (ESI) m / z 531.2 [M−H]+.

[0335] Scheme 7: Synthesis of Compound 18 [ka] Synthesis of 5-hydroxy-N-methoxy-N-methylpentanamide: [ka] To a suspension of the lactone (4 g, 40 mmol, 1 equiv.) and N,O-dimethylhydroxyamine hydrochloride (6.04 g, 1.55 equiv.) in THF (150 ml) at −20° C., a 2.9 M solution of i-PrMgBr in 2-methyltetrahydrofuran (50 ml, 3.6 equiv.) was added dropwise over a period of 30 min. The mixture was stirred at −20° C. for 3 h and quenched with 50 mL of saturated NH4Cl solution. The layers were separated and the aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (eluent 80 / 20 EtOAc / hexane to 100% EtOAc). Yield 2.0 g (31%). NMR (400 MHz, CDCl3): 1.57-1.63 (m, 2H), 1.70-1.76 (m, 2H), 2.44-2.50 (m, 2H), 3.18 (s, 3H), 3.62 (t, 2H), 3.68 (s, 2H). LCMS (C18 column 20 x 2 mm, 2.5 μm particle size, 100 A pore size, water-acetonitrile + 0.1% TFA, 3 min gradient from 5 to 87%, retention time 0.90 min). MS (ESI) m / z 162.4 [M−H]+.

[0336] Synthesis of 5-((tert-butyldiphenylsilyl)oxy)-N-methoxy-N-methylpentanamide: [ka] A mixture of 5-hydroxy-N-methoxy-N-methylpentanamide (2.1 g, 13 mmol, 1 equiv.), tert-butyldiphenylsilyl chloride (5.4 g, 5 mL, 1.5 equiv.), imidazole (1.6 g, 1.8 equiv.), and DMAP (0.16 g, 0.1 equiv.) in DMF (25 mL) was stirred at ambient temperature for 15 h. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3 × 60 mL). The combined organic layers were dried over NaSO, filtered, and the solvent was evaporated. The residue was purified by column chromatography (SiO / hexane, hexane:EtOAc 5:1). Yield 3 g (58.6%). NMR (400 MHz, CDCl3): 1.20 (s, 9H), 1.60-1.66 (m, 2H), 1.70-1.78 (m, 2H), 2.41-2.47 (m, 2H), 3.19 (s, 3H), 3.65 (s, 3H), 3.70 (t, 2H), 7.38-7.44 (m, 6H), 7.66-7.71 (m, 4H). LCMS (C18 column 20 x 2 mm, 2.5 μm particle size, 100 A pore size, water-acetonitrile + 0.1% TFA, 3 min gradient from 5 to 87%, retention time 2.20 min), MS (ESI) m / z 400.5 [M−H]+.

[0337] Synthesis of 7-((tert-butyldiphenylsilyl)oxy)-2-ethoxyhept-1-en-3-one: [ka] A solution of ethyl vinyl ether (1.8 g, 2.4 ml, 3.3 equiv.) in anhydrous tetrahydrofuran (50 mL) was cooled to −78° C., and tert-butyllithium in pentane (1.7 M, 13 ml, 3 equiv.) was added. The mixture was warmed to 0° C. over a 1-hour period, stirred for 45 minutes, and then cooled to −30° C. 5-((tert-butyldiphenylsilyl)oxy)-N-methoxy-N-methylpentanamide (3.0 g, 7.5 mmol, 1 equiv.) in THF was added, and the mixture was stirred at 0° C. for 4 hours. The progress of the reaction was monitored by TLC. The mixture was poured into aqueous NH4Cl and extracted with Et2O. The combined extracts were dried over Na2SO4, filtered, and the solvent was evaporated. The product was used in the next step without further purification. Yield 2.5 g (81%). NMR (400MHz, CDCl3): 1.02 (s, 9H), 1.35 (t, 3H), 1.58-1.62 (m, 2H), 1.70-1.76 (m, 2H), 2.69 (t, 2H), 3.68 (t, 2H), 3.81 (q, 2H), 4.40 (d, 1H), 5.18 (d, 1H), 7.38-7.43 (m, 6H), 7.64-7.68 (m, 4H).

[0338] Synthesis of (2Z,2'E)-2,2'-(7-((tert-butyldiphenylsilyl)oxy)heptane-2,3-diylidene)bis(N-ethylhydrazine-1-carbothioamide): [ka] 7-((tert-Butyldiphenylsilyl)oxy)-2-ethoxyhept-1-en-3-one (2.0 g, 4.9 mmol, 1 equiv.) was dissolved in EtOH (50 ml), and ethyl thiosemicarbazide (1.16 g, 2 equiv.) and 3 drops of H2SO4 were added. The reaction mixture was stirred and heated to reflux for 4 h, then maintained at ambient temperature for 15 h. The formed precipitate was filtered, washed with EtOH, water, Et2O, and dried. Yield 1.71 g (60%). NMR (400MHz, DMSO-d6): 0.88 (s, 9H), 6.72 (t, 6H), 1.40-1.60 (m, 4H), 2.18 (s, 3H), 3.38-3.43 (m, 4H), 3.56-3.62 (m, 4H), 7.38-7.44 (m, 6H), 7.56-7.61 (m, 4H), 10.21-10.23 (m, 2H), 10.38-10.42 (m, 2H).

[0339] Synthesis of INT-18, ((2Z,2'E)-2,2'-(7-hydroxyheptane-2,3-diylidene)bis(N-ethylhydrazine-1-carbothioamide)): [ka] A mixture of (2Z,2'E)-2,2'-(7-((tert-butyldiphenylsilyl)oxy)heptane-2,3-diylidene)bis(N-ethylhydrazine-1-carbothioamide) (1.3 g, 2.3 mmol) and n-tetrabutylammonium fluoride trihydrate (0.88 g, 1.2 equiv.) in THF (25 ml) was stirred at ambient temperature for 15 h. The reaction mixture was diluted with water (150 ml) and extracted with EtOAc (3 x 60 ml). The organic layer was separated, dried over Na2SO4, filtered and the solvent was evaporated. Yield 0.53 g (65%). NMR (400MHz, DMSO-d6): 1.10-1.16 (m, 6H), 1.38-1.48 (m, 4H), 2.19 (s, 3H), 2.84-2.87 (m, 2H), 3.41-3.47 (m, 2H), 3.58-3.62 (m, 4H), 4.50 (t, 1H), 8.26-8.38 (m, 2H), 10.20 (s, 1H), 10.41 (s, 1H).

[0340] Synthesis of compound 18: [ka] Cu(OAc)2·2H2O (0.12 g, 1.1 equiv.) was added to INT-18 (0.18 g, 0.5 mmol, 1 equiv.) in ethanol. The mixture was stirred at ambient temperature for 15 h. The formed complex precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum. Yield: 0.06 g (25%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.74 min). MS (ESI) m / z 408.5 [M−H]+.

[0341] Scheme 8: Synthesis of Compound 19 [ka] Synthesis of (2-aminoethyl)triphenylphosphonium bromide: [ka] A stirred solution of triphenylphosphine (4.3 g, 16.6 mmol) and 2-bromoethylamine hydrobromide (3.4 g, 16.6 mmol) in n-propanol (100 ml) was heated to reflux under a nitrogen atmosphere for 72 hours. The mixture was then cooled to room temperature, and the solid was filtered, washed with portions of dry ether, and dried under vacuum. The product was dissolved in 50 ml of water, the insoluble solid was filtered, and the filtrate was concentrated to dryness in vacuo to give the title compound (6.40 g, 100%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 minutes, retention time 1.25 minutes, MS (ESI) m / z 306.5 [MH]+).

[0342] Synthesis of (4Z,5E)-4,5-bis(2-(methylcarbamothioyl)hydrazinylidene)pentanoic acid: [ka] To a stirred solution of imidazolepropionic acid (0.5 g, 3.6 mmol) in water (18 mL) was added a solution of NBS (0.63 g, 1 equiv.) in acetonitrile (5.5 mL) in one portion. After stirring for 20 minutes, the acetonitrile was removed in vacuo. To the reaction mixture was added a solution of sodium acetate trihydrate (0.7 g) and methyl thiosemicarbazide (1.12 g, 3 equiv.) in water (7.5 mL). Crystals began to form within 5 minutes. Crystallization was continued at ambient temperature for 14 hours, and the precipitate was filtered and recrystallized from water. Yield 0.34 g (31.3%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.10 min, MS (ESI) m / z 305.0 [M−H]+). 1H-NMR (400MHz, DMSO-d6): δ (ppm) 2.41 (br.s, 2H), 2.91 (br.s, 2H), 2.99 (br.s, 6H), 7.60 (s, 1H), 8.29 (br.s, 1H), 8.54 (br.s, 1H), 10.80 (s, 1H), 11.73 (s, 1H).

[0343] Synthesis of INT-19, ((2-((4Z,5E)-4,5-bis(2-(methylcarbamothioyl)hydrazinylidene)pentanamido)ethyl)triphenylphosphonium): [ka] A mixture of (4Z,5E)-4,5-bis(2-(methylcarbamothioyl)hydrazineylidene)pentanoic acid (0.44 g, 1.4 mmol), (2-aminoethyl)triphenylphosphonium bromide (0.55 g, 1 equiv.), EDCI (0.3 g, 1.1 equiv.), and HOBT (0.21 g, 1.1 equiv.) in DMF (15 ml) was stirred at room temperature overnight. The reaction mixture was diluted with water (50 ml) and extracted with dichloromethane (3 × 20 ml). The extracts were dried over NaSO, filtered, and evaporated. Yield 0.2 g (23.3%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.17 min, MS (ESI) m / z 592.8 [M−H]+).

[0344] Synthesis of INT-20, ((2-((4Z,5E)-4,5-bis(2-carbamothioylhydrazinylidene)pentanamido)ethyl)triphenylphosphonium): [ka] INT-20 was made using a procedure similar to that for preparing INT-19. Yield 0.76 g (74.4%). 1H-NMR (400MHz, DMSO-d6): δ (ppm) 2.30-2.43 (m, 2H), 2.77-2.92 (m, 2H), 7.59 (s, 1H), 7.80 (br.s, 1H), 7.92 (br.s,1H), 8.33 (br.s, 1H), 8.39 (br.s, 1H), 10.76 (s, 1H), 11.65 (s, 1H).

[0345] Synthesis of INT-21, ((2-((4Z,5E)-4,5-bis(2-(ethylcarbamothioyl)hydrazinylidene)pentanamido)ethyl)triphenylphosphonium) [ka] INT-21 was made using a procedure similar to that for preparing INT-19. Yield: 0.76 g (74.4%). LCMS (C18 column 20 x 2 mm, 2.5 μm particle size, 100 A pore size, water-acetonitrile + 0.1% TFA, 3 min gradient from 5 to 87%, retention time 1.33 min, MS (ESI) m / z 620.5 [M-H]+). 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 1.00-1.21 (m, 6H), 2.29 (br.s, 2H), 2.87 (br.s, 2H), 3.34 (br.s, 2H), 3.49-3.55 (m, 4H), 3.65-3.77 (m, 2H), 7.58 (s, 1H), 7.77-7.96 (m, 15H), 8.41 (br.s, 1H), 8.53 (br.s, 1H), 8.60 (br.s, 1H), 10.74 (s, 1H), 11.74 (s, 1H).

[0346] Synthesis of compound 19: [ka] Cu(OAc)2·2H2O (0.025 g, 1.1 equiv.) was added to INT-19 (0.087 g, 0.1 mmol, 1 equiv.) in ethanol. The mixture was stirred at ambient temperature for 15 h. The formed complex precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum. Yield: 0.018 g (19%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.56 min). MS (ESI) m / z 653.3 [M−H]+.

[0347] Synthesis of compound 20: [ka] The title compound was prepared from INT-20 according to the procedure for preparing compound 19. The product precipitated from the reaction mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum. Yield 0.09 g (45%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.49 min). MS (ESI) m / z 625.3 [M−H]+.

[0348] Synthesis of compound 21: [ka] The title compound was prepared from INT-21 according to the procedure for preparing compound 19. The product precipitated from the reaction mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum. Yield 0.09 g (45%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.79 min). MS (ESI) m / z 681.2 [M−H]+.

[0349] Scheme 9: Synthesis of compound 22 [ka] Synthesis of 2-(2-methoxyethoxy)acetyl chloride: [ka] To a solution of acid 1 (5.0 g, 37 mmol) in CHCl (100 mL) was added a few drops of DMF followed by SOCl (13.3 g, 3 equiv.), and the mixture was stirred at ambient temperature for 15 h. Evaporation of the solvent gave compound 2 (4.4 g, 78%), which was used in the next step without further purification. NMR (400 MHz, CDCl): 3.37 (s, 3H), 3.57-3.60 (m, 2H), 3.74-3.78 (m, 2H), 4.50 (s, 2H).

[0350] Synthesis of N-methoxy-2-(2-methoxyethoxy)-N-methylacetamide: [ka] To a solution of 2-(2-methoxyethoxy)acetyl chloride (4.4 g, 29 mmol) in CHCl (100 mL) was added N,O-dimethylhydroxylamine hydrochloride (3.4 g, 1.2 equiv.), followed by EtN (11.7 g, 4 equiv.). The mixture was stirred at ambient temperature for 15 h, quenched with 10% aqueous HCl, and extracted with EtOAc. The combined organic extracts were dried over NaSO, filtered, and the solvent was evaporated. The residue was purified on silica gel eluting with a gradient of 10% to 75% EtOAc in hexane to give compound (3) (2.7 g, 53%). NMR (400MHz, CDCl3): 3.18 (s, 3H), 3.39 (s, 3H), 3.57-3.64 (m, 2H), 3.68 (s, 3H), 3.73-3.77 (m, 2H), 4.34 (s, 2H).

[0351] Synthesis of 3-ethoxy-1-(2-methoxyethoxy)but-3-en-2-one: [ka] A solution of ethyl vinyl ether (2.0 g, 2.7 ml, 3.3 equiv.) in anhydrous tetrahydrofuran (75 mL) was cooled to −78° C., and tert-butyllithium in pentane (1.7 M, 15 ml, 3 equiv.) was added. The mixture was warmed to 0° C. over a 1-hour period, stirred for 45 minutes, and then cooled to −30° C. N-Methoxy-2-(2-methoxyethoxy)-N-methylacetamide (1.53 g, 8.6 mmol, 1 equiv.) in THF was added, and the mixture was stirred at 0° C. for 4 hours. The progress of the reaction was monitored by TLC. The mixture was poured into aqueous NH4Cl and extracted with Et2O. The combined extracts were dried over Na2SO4, filtered, and the solvent was evaporated. The product was used in the next step without further purification. Yield 0.73g(45%), NMR (400MHz, DMSO-d6): 1.28 (t, 3H), 3.22 (s, 3H), 3.32 (s, 2H), 3.42-3.46 (m, 2H), 3.53-3.58 (m, 2H), 4.52 (s, 2H), 4.62 (d, 1H), 5.10 (d, 1H).

[0352] Synthesis of INT-22, ((2Z,2'E)-2,2'-(1-(2-methoxy)butane-2,3-diylidene)bis(N-methylhydrazine-1-carbothioamide)): [ka] 3-Ethoxy-1-(2-methoxyethoxy)but-3-en-2-one (0.73 g, 3.9 mmol, 1 equiv.) was dissolved in EtOH (100 ml), and methyl thiosemicarbazide (0.82 g, 2 equiv.) and 3 drops of H2SO4 were added. The reaction mixture was stirred and heated to reflux for 4 h, then maintained at ambient temperature for 15 h. The formed precipitate was filtered, washed with EtOH, water, Et2O, and dried. Yield 0.2 g (15%). NMR (400 MHz, DMSO-d6): 2.20 (s, 3H), 3.02, 3.04 (m, 6H), 3.28 (s, 3H), 3.48-3.60 (m, 4H), 4.84 (s, 2H), 8.38-8.50 (m, 2H), 10.23 (s, 1H), 10.58 (s, 1H). LCMS (C18 column 20 x 2 mm, 2.5 μm particle size, 100 A pore size, water-acetonitrile with 0.1% TFA, 3 min gradient from 5 to 87%, retention time 1.34 min). MS (ESI) m / z 335.6 [M−H]+.

[0353] Synthesis of compound 22: [ka] Cu(OAc)2·2H2O (0.16 g, 1.1 equiv.) was added to thiosemacarbazone 5 (0.2 g, 0.66 mmol, 1 equiv.) in ethanol. The mixture was stirred at ambient temperature for 15 h. The formed complex precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum. Yield: 0.06 g (25%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.77 min). MS (ESI) m / z 396.3 [M−H]+.

[0354] Example 2: Preparation of Compounds 23-46 Synthesis of INT-25, ((2Z,2'E)-2,2'-(1-(furan-2-yl)propane-1,2-diylidene)bis(N-methylhydrazine-1-carbothioamide)): [ka] INT-25 was made using a procedure similar to that for preparing INT-1 in Example 1. Yield 6.78 g (78%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.34 min). MS (ESI) m / z 313.4 [M−H]+. 1 H-NMR (400MHz, CDCl3): δ (ppm) 2.25 (s, 3H), 3.20 (s, 3H), 3.28 (s, 3H), 6.62 (d, 1H), 6.84 (d, 1H), 7.31 (s, 1H), 7.33 (s, 1H), 7.53 (s, 1H), 7.71 (s, 1H), 8.79 (s,1H), 10.52 (s, 1H).

[0355] Synthesis of INT-33, ((2E,2'E)-2,2'-(1-(2,5-dimethylfuran-3-yl)propane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide)): [ka] INT-33 was made using a procedure similar to that for preparing INT-1 in Example 1. Yield 1.8 g (48%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.60 min). MS (ESI) m / z 369.5 [M−H]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 1.07 (t, 3H), 1.15 (t, 3H), 2.06 (s, 3H), 2.28 (s, 3H), 2.30 (s, 3H), 3.41-3.48 (m, 2H), 3.55-3.63 (m, 2H), 6.09 (s, 1H), 6.84 (d, 1H), 7.37 (t, 1H), 8.69 (t, 1H), 9.52-10.52 (m, 1H).

[0356] Synthesis of INT-41, ((2E,2'E)-2,2'-(1-(1-ethyl-1H-pyrazol-5-yl)propane-1,2-diylidene)bis(N-methylhydrazine-1-carbothioamide)): [ka] INT-41 was made using a procedure similar to that for preparing INT-1 in Example 1. Yield 0.55 g (52.9%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 0.83 min, MS (ESI) m / z 341.3 [M-H]+).

[0357] Synthesis of compound 25: [ka] The title compound was prepared from INT-25 according to the method for preparing compound 1 in Example 1. Yield 6.2 g (76%). ICP / MS sulfur: 17.36%, copper: 16.518%. LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 2.11 min). MS (ESI) m / z 374.1 [M−H]+.

[0358] Synthesis of compound 33: [ka] The title compound was prepared from INT-33 according to the method for preparing compound 1 in Example 1. The product was isolated as a reddish-brown powder. After cooling, the precipitate formed was collected by filtration, washed with water (2 x 50 ml), ethanol (2 x 50 ml), and a large amount of diethyl ether (5 x 50 ml), and then dried under vacuum. Yield 0.7 g (75%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 2.34 min). MS (ESI) m / z 430.5 [M−H]+.

[0359] Synthesis of compound 41: [ka] The title compound was prepared from INT-41 according to the method for preparing compound 1 in Example 1. The product precipitated from the reaction mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum. Yield 0.18 g (55.7%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.80 min). MS (ESI) m / z 401.8 [M−H]+.

[0360] Scheme 10: Synthesis of compound 23 [ka] Synthesis of methyl 5-(3-oxopropyl)furan-2-carboxylate: [ka] To a stirred solution of methyl 5-bromofuroate (5.7 g, 28 mmol, 1 equiv.) in DMF (550 ml) under an inert atmosphere, allyl alcohol (2.28 g, 1.4 equiv.), Pd(OAc) (0.189 g, 0.03 equiv.), TEBAC (6.39 g, 1 equiv.), and NaCO (6.85 g, 2 equiv.) were added. The mixture was then stirred at 80 °C for 2 h. Once the reaction reached completion, the resulting mixture was filtered through Celite, concentrated in vacuo at ≤ 40 °C, diluted with ethyl acetate, washed with brine, concentrated to dryness in vacuo, and the residue was purified by column chromatography (ethyl acetate:hexane 1:3). Yield 2.7 g (53%). 1 H-NMR (400MHz, CDCl3): δ (ppm) 2.89(dd, 2H), 3.05(dd, 2H), 3.89(s, 3H), 6.19(s, 1H), 7.09(s, 1H), 9.83(s, 1H).

[0361] Synthesis of methyl 5-(3-morpholinopropyl)furan-2-carboxylate: [ka] Methyl 5-(3-oxopropyl)furan-2-carboxylate (1.6 g, 9 mmol, 1 equiv.) was dissolved in MeOH (90 ml), and molecular sieves 3A (2.64 g) were added to the solution. After stirring for 15 min, the mixture was cooled to 0 °C. To the stirred solution of the aldehyde, a solution of morpholine (1.15 g, 1.5 equiv.) and acetic acid (1.05 g, 2 equiv.) in methanol (42 ml) was added. After stirring for 2 min, NaBH CN (1.66 g, 3 equiv.) was added. The resulting mixture was stirred at 0 °C for 14 h and allowed to reach ambient temperature. The reaction mixture was diluted with DCM, filtered through Celite, and the filtrate was washed with aqueous NaHCO . The aqueous phase was extracted twice with DCM. The organic phase was dried over Na SO , filtered, and the solvent was evaporated. The residue was purified by column chromatography (SiO2, eluting with 1:5 to 1:3 to 1:1 to 100% EtOAc-hexane, followed by 10:1 CHCl-MeOH). Yield 1.5 g (68%). LCMS (C18 column 20 × 2 mm, 2.5 μm particle size, 100 Å pore size, water-acetonitrile + 0.1% TFA, 3 min gradient from 5 to 87%, retention time 0.28 min. MS (ESI) m / z 254.4 [M−H]+, retention time 0.8 min. MS (ESI) m / z 254.6 [M−H]+. 1 H-NMR (400MHz, CDCl3): δ (ppm) 1.86-1.94 (m, 2H), 2.39-2.44 (m, 2H), 2.44-2.53(m, 4H), 2.66-2.86(m, 2H), 3.68-3.77(m, 4H), 3.88(s, 3H), 6.16(d, 1H), 7.11(d, 1H).

[0362] Synthesis of 5-(3-morpholinopropyl)furan-2-carboxylic acid: [ka] To a solution of methyl 5-(3-morpholinopropyl)furan-2-carboxylate (1.5 g, 6.0 mmol) in methanol (20 ml) was added a solution of NaOH (0.6 g, 2 equivalents) in water (5 ml), and the reaction mixture was stirred overnight at room temperature. The methanol was removed in vacuo, and the residue was diluted with water and acidified to pH 1. The acidified solution was evaporated to dryness in vacuo and treated with isopropanol. The solid salt was filtered, and the filtrate was evaporated to dryness in vacuo. Yield: 1.4 g (73.5%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 0.28 min). MS (ESI) m / z 240.4 [M-H]+, retention time 0.67 min. MS (ESI) m / z 240.1 [M-H]+. 1 H-NMR (400MHz, CDCl3): δ (ppm) 1.98-2,15 (m,2H), 2.68-2.80 (m, 2H), 2.91-3.17(m, 4H), 3.37-3.49(m, 2H), 3.75-3.99(m, 4H), 6.41(s, 1H), 7.14(s, 1H), 11.26(br.s, 1H), 12.91(br.s, 1H).

[0363] Synthesis of N-methoxy-N-methyl-5-(3-morpholinopropyl)furan-2-carboxamide: [ka] To a stirred mixture of 5-(3-morpholinopropyl)furan-2-carboxylic acid (1.2 g, 4.0 mmol, 1 equiv.), N,O-dimethylhydroxylamine (0.55 g, 1.3 equiv.), HOBt (0.65 g, 1.1 equiv.), and DIPEA (3 mL, 4 equiv.) in CHCl (25 mL) at 5° C. was added EDCI (0.83 g, 1 equiv.). The reaction was stirred at ambient temperature for 15 h. The mixture was washed with water and brine. The organic layer was dried over anhydrous NaSO, filtered, and the solvent was concentrated under reduced pressure. The product was used without further purification. Yield 0.9 g (73%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 0.34 min. MS (ESI) m / z 283.6 [M−H]+, retention time 0.85 min. MS (ESI) m / z 283.5 [M−H]+. 1 H-NMR (400MHz, CDCl3): δ (ppm) 1.86-1.94 (m,2H), 2.40-2.53 (m, 6H), 2.71-2.81(m, 2H), 3.34(s, 3H), 3.68-3.74(m, 4H), 3.76(s,3H), 6.15(d, 1H), 7.07(d, 1H).

[0364] Synthesis of 1-(5-(3-morpholinopropyl)furan-2-yl)ethan-1-one: [ka] A solution of N-methoxy-N-methyl-5-(3-morpholinopropyl)furan-2-carboxamide (0.9 g, 3.0 M, 1 eq.) in THF (50 ml) was cooled to 5° C., and a solution of methylmagnesium bromide in THF (3.4 M, 2.8 ml, 3 eq.) was added. The reaction mixture was stirred at 5° C. for 2 h, poured into aqueous NH4Cl, and extracted with Et2O. The combined extracts were dried over Na2SO4 and evaporated. The title product was used in the next step without purification. Yield 0.6 g (79%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 0.3 min, MS (ESI) m / z 238.4 [MH]+, retention time 0.8 min, MS (ESI) m / z 238.4 [MH]+). 1 H-NMR (400MHz, CDCl3): δ (ppm) 1.88-1.96 (m, 2H), 2.35-2.64 (m, 9H), 2.73-2.79 (m, 2H), 3.66-3.90 (m, 4H), 6.20 (s, 1H), 7.11 (s, 1H).

[0365] Synthesis of INT-23, ((2E,2'E)-2,2'-(1-(5-(3-morpholinopropyl)furan-2-yl)ethane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide)): [ka] A mixture of 1-(5-(3-morpholinopropyl)furan-2-yl)ethan-1-one (0.5 g, 2.0 mmol, 1 equiv.), NaBr (0.11 g, 0.5 equiv.), and DMSO (1.1 mL) was heated to 85 °C, and then H2SO4 (6 drops) was added (foaming), causing the reaction temperature to begin to rise. The reaction was heated to 110–115 °C, until the formation of dimethyl sulfide ceased and the reaction mixture became viscous. The viscous material that formed was dissolved in EtOH, and to this solution was added ethyl thiosemicarbazide (0.5 g, 2 equiv.). The reaction mixture was refluxed for 2 h, then cooled to room temperature. The solvent was evaporated in vacuo, and the residue was dissolved in water (25 mL), neutralized with saturated aqueous Na2CO3, and extracted with EtOAc (3 × 50 mL). The organic layer was separated, dried over Na2SO4, filtered, and the solvent was evaporated. The residue was treated with water. The precipitate that formed was filtered and washed with EtOH to give the pure title compound. Yield 0.2 g (21%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.18 min, MS (ESI) m / z 454.4 [M-H]+).

[0366] Synthesis of INT-27, ((2E,2'E)-2,2'-(1-(5-(3-morpholinopropyl)furan-2-yl)ethane-1,2-diylidene)bis(N-methylhydrazine-1-carbothioamide)): [ka] INT-21 was made using a procedure similar to that for preparing INT-19. Yield: 0.16 g (15%). LCMS (C18 column 20 x 2 mm, 2.5 μm particle size, 100 A pore size, water-acetonitrile + 0.1% TFA, 5 to 87% gradient in 3 min, retention time 1.02 min, MS (ESI) m / z 426.3 [M-H]+).

[0367] Synthesis of compound 23: [ka] CuCl2·2H2O (0.034 g, 1 equiv.) was added to thiosemicarbazone 6 (0.09 g, 0.2 mmol, 1 equiv.) in ethanol. The mixture was stirred at ambient temperature for 15 h. The formed complex precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum. Yield 0.05 g (48%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.56 min). MS (ESI) m / z 515.4 [M−H]+.

[0368] Synthesis of compound 27: [ka] The title compound was prepared from INT-27 according to the procedure for preparing compound 23. The product precipitated from the reaction mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum. Yield 0.095 g (87%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.46 min). MS (ESI) m / z 487.5 [M−H]+.

[0369] Scheme 11: Synthesis of compound 31 [ka] Synthesis of ethyl 5-(1-chloroethyl)furan-2-carboxylate: [ka] Zinc chloride (3.9 g, 28.6 mmol) was added to a solution of paraldehyde (17.3 g, 131.1 mmol) and ethyl 2-furoate (16.9 g, 120.7 mmol) in chloroform (36 mL). Hydrogen chloride was passed through the mixture with vigorous stirring at 25-30 °C for 5 h. 250 mL of chloroform was then added, and the reaction mixture was washed with water (2 × 30 mL) and then dried over calcium chloride. The solvent was removed under reduced pressure to give the desired product 1, which was used in the next step without further purification. Yield 35 g (31%). 1 H-NMR (400MHz, CDCl3): δ (ppm) 1.18 (d, 3H), 1.33 (t, 3H), 4.32 (q, 2H), 5.09 (q, 1H), 6.41 (d,1H), 7.07 (d, 1H).

[0370] Synthesis of ethyl 5-(1-(piperidin-1-yl)ethyl)furan-2-carboxylate: [ka] A suspension of ethyl 5-(1-chloroethyl)furan-2-carboxylate (5.0 g, 24.6 mmol), piperidine (4.2 g, 49.2 mmol), and potassium carbonate (6.8 g, 49.2 mmol) in CHCN (100 mL) was stirred at 50 °C for 12 h. The mixture was cooled to room temperature. CHCN was removed by evaporation, and the residue was diluted with 20 mL of 2 N aqueous sodium carbonate solution and extracted with dichloromethane. The organic phase was washed with brine, dried over NaSO, filtered, and evaporated to dryness. The residue was purified by column chromatography (silica gel, eluent 100% DCM to 5% MeOH) to give the title product, which was used in the next step without further purification. Yield 5.1 g (82%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 0.90 min). MS (ESI) m / z 252.1 [MH]+. 1H-NMR (400MHz, CDCl3): δ (ppm) 1.36 (d, 2H), 1.38 (d, 3H), 1.44 (d, 3H), 1.58 (q, 4H), 2.35-2.41 (m, 2H), 2.48-2.53 (m, 2H), 3.81 (q, 1H), 4.35 (q, 2H), 6.29 (d, 1H), 7.17 (d, 1H).

[0371] Synthesis of 5-(1-(piperidin-1-yl)ethyl)furan-2-carboxylic acid: [ka] A solution of ethyl 5-(1-(piperidin-1-yl)ethyl)furan-2-carboxylate (5.1 g, 20.3 mmol) in MeOH (50 ml) was added to a 20% aqueous solution of LiOH (1.6 g, 60.9 mmol). The reaction mixture was stirred at 60° C. for 8 hours. The solvent was then removed by lyophilization, and the corresponding crude product was used in the next step without further purification. Yield 4.4 g (83%). LCMS (C18 column 20×2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile+0.1% TFA, gradient 5 to 87% in 3 min, retention time 0.65 min). MS (ESI) m / z 224.4 [M−H]+. 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 1.33-1.38 (m, 2H), 1.43 (d, 3H), 1.57-1.61 (m, 4H), 2.07 (s, 1H), 2.60-2.63 (m, 2H), 4.07 (q, 2H), 4.32 (s, 1H), 6.52 (d, 1H), 7.04 (d, 1H).

[0372] Synthesis of N-methoxy-N-methyl-5-(1-(piperidin-1-yl)ethyl)furan-2-carboxamide: [ka] To a stirred mixture of 5-(1-(piperidin-1-yl)ethyl)furan-2-carboxylic acid (5.2 g, 20 mmol), N,O-dimethylhydroxylamine (2.3 g, 24 mmol), HOBt (3.2 g, 24 mmol), and TEA (12 ml, 90 mol) in DCM (80 ml) at 4 °C, EDCI (4.6 g, 24 mmol) was added, and the mixture was then stirred at room temperature overnight. The mixture was washed with water (15 ml) and brine (100 ml). The organic layer was dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent 100% DCM to 5% MeOH) to give the crude product. Yield 2.2 g (42%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 0.77 min). MS (ESI) m / z 267.5 [M−H]+. 1 H-NMR (400MHz, CDCl3): δ (ppm) 1.38 (t, 2H), 1.46 (d, 3H), 1.54-1.60 (m, 4H), 2.36-2.41 (m, 2H), 2.50-2.55 (m, 2H), 3.33 (s, 3H), 3.78 (s, 3H), 3.81-3.87 (m, 1H), 6.26 (dd, 1H), 7.23 (dd, 1H).

[0373] Synthesis of 2-ethoxy-1-(5-(1-(piperidin-1-yl)ethyl)furan-2-yl)prop-2-en-1-one: [ka] A solution of ethyl vinyl ether (1.8 g, 24.4 mmol) in tetrahydrofuran (50 ml) was cooled to −78° C., and tert-butyllithium in pentane (1.7 M, 14.0 ml, 22.2 mmol) was added. The mixture was warmed to 0° C. over a period of 1 hour, stirred for 45 minutes, and cooled to −30° C. A solution of N-methoxy-N-methyl-5-(1-(piperidin-1-yl)ethyl)furan-2-carboxamide (1.0 g, 3.7 mmol) in THF (15 ml) was added, and the mixture was stirred at 0° C. for 4 hours. The progress of the reaction was monitored by TLC. The mixture was poured into aqueous NH4Cl (100 ml) and extracted with Et2O (3 × 50 ml). The combined extracts were dried over Na2SO4. The product solution was then decanted, and the solvent was removed under reduced pressure to give the title compound, which was used in the next step without further purification. Yield 1.1 g (87%). LCMS (C18 column 20 x 2 mm, 2.5 μm particle size, 100 A pore size, water-acetonitrile + 0.1% TFA, 3 min gradient from 5 to 87%, retention time 0.97 min). MS (ESI) m / z 278.6 [M−H]+. 1 H-NMR (400MHz, CDCl3): δ (ppm) 1.38 (t, 2H), 1.46 (d, 3H), 1.47 (d, 3H), 1.55-1.63 (m, 4H), 2.38-2.44 (m, 2H), 2.51-2.56 (m, 2H), 3.81-3.87 (m, 1H), 3.93 (q, 2H), 4.58 (d, 1H), 5.33 (d, 1H), 6.31 (d, 1H), 7.47 (d, 1H).

[0374] Synthesis of INT-31, ((2Z,2'E)-2,2'-(1-(5-(1-(piperidin-1-yl)ethyl)furan-2-yl)propane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide)) [ka] 2-Ethoxy-1-(5-(1-(piperidin-1-yl)ethyl)furan-2-yl)prop-2-en-1-one (1.1 g, 3.7 mmol) was dissolved in EtOH (30 mL), and ethyl thiosemicarbazide (0.9 g, 7.4 mmol) and 3 drops of H2SO4 were added. The stirred reaction mixture was heated to reflux for 4 h and then maintained at ambient temperature overnight. The reaction progress was monitored by TLC (CCl4 / EtOAc 7:3). The precipitate was filtered, washed with EtOH, water, Et2O, and dried. Yield 0.5 g (33%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile with 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.17 min). MS (ESI) m / z 452.0 [M−H]+. 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 1.07 (t, 3H), 1.15 (t, 3H), 1.38-1.55 (m, 3H),1.60-1.66 (m, 4H), 1.70-1.79 (m, 4H), 2.33 (s, 3H), 3.41-3.48 (m, 2H), 3.55-3.63 (m, 2H), 4.72 (s, 1H), 6.91 (dd, 1H), 7.14 (dd, 1H), 7.73 (t, 1H), 8.73 (t, 1H), 9.08-9.78 (m, 2H), 10.48 (s, 1H), 10.55 (s, 1H).

[0375] Synthesis of INT-24, ((2E,2'E)-2,2'-(1-(5-(morpholinomethyl)furan-2-yl)propane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide)): [ka] INT-24 was made using a procedure similar to that for preparing INT-31. Yield: 4.6 g (63%). LCMS (C18 column 20 x 2 mm, 2.5 μm particle size, 100 A pore size, water-acetonitrile + 0.1% TFA, 3 min gradient from 5 to 87%, retention time 1.01 min). MS (ESI) m / z 440.5 [M−H]+.1 H-NMR (400MHz, DMSO-d6): δ (ppm) 1.10 (t, 3H), 1.16 (t, 3H), 1.39 , 2.32 (s, 3H), 2.35-2.47 (m, 4H), 3.42-3.58 (m, 2H), 3.58-3.76 (m, 8H), 6.61 (s, 1H), 7.01 (s, 1H), 7.78 (br.s, 1H), 8.70 (br.s, 1H), 10.40 (s, 1H), 10.51 (s, 1H).

[0376] Synthesis of INT-32, ((2E,2'E)-2,2'-(1-(5-(morpholinomethyl)furan-2-yl)propane-1,2-diylidene)bis(N-methylhydrazine-1-carbothioamide)): [ka] INT-32 was made using a procedure similar to that for preparing INT-31. Yield: 0.25 g (54%). LCMS (C18 column 20 x 2 mm, 2.5 μm particle size, 100 A pore size, water-acetonitrile + 0.1% TFA, 3 min gradient from 5 to 87%, retention time 1.06 min). MS (ESI) m / z 412.4 [M-H]+. 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 2.33 (s, 3H), 2.92-3.00(m, 4H), 3.03-3.10(m, 4H), 3.12-3.45(m, 4H), 3.70-3.82(m, 4H), 4.5(s, 3H), 6.9(s, 1H), 7.07(s, 1H), 7.71(s, 1H), 8.67(s, 1H), 10.39(s, 1H), 10.54(s, 1H).

[0377] Synthesis of INT-37, ((2E,2'E)-2,2'-(1-(5-((4-methylpiperazin-1-yl)methyl)furan-2-yl)propane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide)): [ka] INT-37 was made using a procedure similar to that for preparing INT-31. Yield 0.9 g (61.5%). LCMS (C18 column 20 x 2 mm, 2.5 μm particle size, 100 A pore size, water-acetonitrile + 0.1% TFA, 3 min gradient from 5 to 87%, retention time 1.06 min). MS (ESI) m / z 453.5 [M−H]+. 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 1.10 (t, 3H), 1.16 (t, 3H), 1.39 , 2.32 (s, 3H), 2.55-2.74 (m, 2H), 2,79-2.89 (M, 4H), 3.42-3.59 (m, 6H), 3.62 (q, 2H), 3.97 (s, 3H), 6.71 (s, 1H), 7.08 (s, 1H), 7.76 (s, 1H), 8.74 (s, 1H), 10.44 (s, 1H), 10.54 (s, 1H).

[0378] Synthesis of INT-39, ((2Z,2'E)-2,2'-(1-(5-(1-morpholinoethyl)furan-2-yl)propane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide)): [ka] INT-39 was made using a procedure similar to that for preparing INT-31. Yield 0.2 g (20%). LCMS (C18 column 20 x 2 mm, 2.5 μm particle size, 100 A pore size, water-acetonitrile + 0.1% TFA, 3 min gradient 5 to 87%, retention time 1.11 min). MS (ESI) m / z 454.3 [M−H]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 1.10 (t, 3H), 1.16 (t, 3H), 1.39 (dd, 3H), 2.32 (s, 3H), 2.34-2.38 (m, 2H), 2.47-2.49 (m, 2H), 3.48-3.53 (m, 2H), 3.56-3.65 (m, 4H),3.60-3.65 (m, 2H), 3.84-3.90 (m, 1H), 6.56 (dd, 1H), 7.06 (dd, 1H), 7.87 (t, 1H), 8.70 (t, 1H), 10.47 (d, 1H), 10.59 (d, 1H).

[0379] Synthesis of compound 31: [ka] CuCl2·2H2O (0.2 g, 2.4 mmol) was added to compound 6 (0.5 g, 1.2 mmol) in 30 ml of ethanol. The mixture was stirred at ambient temperature for 15 h. After cooling, the formed precipitate was collected by filtration, washed with water (2 × 50 ml), ethanol (2 × 50 ml), and a large amount of diethyl ether (5 × 50 ml), and then dried under vacuum. Yield: 0.4 g (75%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.66 min). MS (ESI) m / z 513.3 [M−H]+.

[0380] Synthesis of compound 24: [ka] The title compound was prepared from INT-24 according to the procedure for preparing compound 31. The product precipitated from the reaction mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum. Yield 4.7 g (92%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.48 min). MS (ESI) m / z 501.3 [M−H]+.

[0381] Synthesis of compound 32: [ka] The title compound was prepared from INT-32 according to the procedure for preparing compound 31. The product precipitated from the reaction mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum. Yield 0.14 g (97%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.38 min). MS (ESI) m / z 473.0 [M−H]+.

[0382] Synthesis of compound 37: [ka] The title compound was prepared from INT-37 according to the procedure for preparing compound 31. The product precipitated from the reaction mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum. Yield 0.8 g (96%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.52 min). MS (ESI) m / z 514.3 [M−H]+.

[0383] Synthesis of compound 39: [ka] The title compound was prepared from INT-39 according to the procedure for preparing compound 31. The product precipitated from the reaction mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water (2 x 50 ml), ethanol (2 x 50 ml), and copious amounts of diethyl ether (5 x 50 ml), and then dried under vacuum. Yield 0.15 g (86%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.57 min). MS (ESI) m / z 515.2 [M−H]+.

[0384] Scheme 12: Synthesis of compound 26 [ka] Synthesis of methyl 5-(3-oxopropyl)furan-2-carboxylate: [ka] Under an inert atmosphere, methyl 5-bromofuroate (5.7 g, 28 mmol, 1 equiv.) was dissolved in 550 ml of DMF. Allyl alcohol (2.28 g, 1.4 equiv.), Pd(OAc) (0.189 g, 0.03 equiv.), TEBAC (6.39 g, 1 equiv.), and NaCO (6.85 g, 2 equiv.) were added. The mixture was then stirred at 80 °C for 2 h. Upon completion, the resulting mixture was filtered through Celite, and the filtrate was concentrated under vacuum at ≤ 40 °C, diluted with ethyl acetate, washed with brine, and concentrated to dryness. The residue was purified by column chromatography (silica gel, ethyl acetate-hexane 1:3). Yield: 2.7 g (53%). 1 H-NMR (400MHz, CDCl3): δ (ppm) 2.89(dd, 2H), 3.05(dd, 2H), 3.89(s, 3H), 6.19(s, 1H), 7.09(s, 1H), 9.83(s, 1H).

[0385] Synthesis of methyl 5-(3-(piperidin-1-yl)propyl)furan-2-carboxylate: [ka] Methyl 5-(3-oxopropyl)furan-2-carboxylate (2.7 g, 15 mmol, 1 equiv.) was dissolved in MeOH (150 ml), and molecular sieves (4.4 g) were added to the solution. After stirring for 15 min, the mixture was cooled to 0 °C. To the stirred solution of aldehyde 1, a solution of piperidine (1.9 g, 1.5 equiv.) and acetic acid (1.8 g, 2 equiv.) in methanol (70 ml) was added at 0 °C. After stirring for 2 min, NaBH CN (2.8 g, 3 equiv.) was added. The resulting mixture was stirred for 14 h, allowing it to warm from 0 °C to room temperature. The reaction mixture was then diluted with DCM, filtered through Celite, and the filtrate was washed with aqueous NaHCO . The aqueous phase was extracted twice with DCM. The organic phase was dried over Na SO , filtered, and concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2, first eluting with a gradient of 1:5 to 1:3 to 1:1 to 100% EtOAc / hexanes, then with 10:1 CHCl / MeOH). Yield 1.8 g (49%). LCMS (C18 column 20 × 2 mm, 2.5 μm particle size, 100 Å pore size, water-acetonitrile + 0.1% TFA, 5 to 87% gradient in 3 min, retention time 0.94 min). MS (ESI) m / z 252.4 [M−H]+. 1 H-NMR (400MHz, CDCl3): δ (ppm) 1.45-1.66 (m,2H), 1.78-1.88 (m, 2H), 1.96-2.17(m, 4H), 2.57-2.88(m, 6H), 3.41-3.56(m, 2H), 3.88(s, 3H), 6.23(s, 1H), 7.09(s, 1H).

[0386] Synthesis of 5-(3-(piperidin-1-yl)propyl)furan-2-carboxylic acid: [ka] To a stirred solution of methyl 5-(3-(piperidin-1-yl)propyl)furan-2-carboxylate (1.8 g, 7.0 mmol) in methanol (20 ml) was added a solution of NaOH (0.73 g, 2.6 equiv.) in water (25 ml). The reaction mixture was stirred at ambient temperature for 15 hours. The methanol was removed in vacuo and the residue was diluted with water and acidified to pH 1. The acidified solution was evaporated to dryness and the residue was treated with isopropanol. The solid salts were filtered and the filtrate was evaporated to dryness. Yield 1.35 g (68%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 0.35 min. MS (ESI) m / z 238.3 [M-H]+, retention time 0.86 min. MS (ESI) m / z 238.3 [M-H]+.

[0387] Synthesis of N-methoxy-N-methyl-5-(3-(piperidin-1-yl)propyl)furan-2-carboxamide: [ka] To a mixture of methyl 5-(3-(piperidin-1-yl)propyl)furan-2-carboxylate (1.35 g, 5.0 M, 1 equiv.), N,O-dimethylhydroxylamine (0.72 g, 1.3 equiv.), HOBt (0.83 g, 1.1 equiv.), and DIPEA (3.3 ml, 4 equiv.) in CHCl (25 ml) at 5° C. was added EDCI (1.04 g, 1.1 equiv.). The reaction was then stirred at ambient temperature for 15 h. The mixture was washed with water and brine. The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The product was used further without purification. Yield 0.4 g (29%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 0.35 min. MS (ESI) m / z 281.5 [M-H]+, retention time 0.93 min. MS (ESI) m / z 281.3 [M-H]+. 1H-NMR (400MHz, CDCl3): δ (ppm) 1.38-1.48 (m,2H), 1.55-1.64(m, 4H), 1.86-1.97(m, 2H), 2.31-2.48(m, 6H), 2.69-2.81(m, 2H), 3.34(s, 3H), 3.76(s, 3H), 6.14(d, 1H), 7.07(d, 1H).

[0388] Synthesis of 2-ethoxy-1-(5-(3-(piperidin-1-yl)propyl)furan-2-yl)prop-2-en-1-one: [ka] A solution of ethyl vinyl ether (0.72 g, 0.96 ml, 7 equiv.) in anhydrous tetrahydrofuran (20 mL) was cooled to −78° C., and tert-butyllithium in pentane (1.7 M, 5 ml, 6 q.) was added. The mixture was warmed to 0° C. over a 1-hour period, stirred for 45 minutes, and cooled to −30° C. A solution of N-methoxy-N-methyl-5-(3-(piperidin-1-yl)propyl)furan-2-carboxamide (0.4 g, 1.4 mmol, 1 equiv.) in THF was added, and the mixture was stirred at 0° C. for 4 hours. The progress of the reaction was monitored by TLC. The mixture was poured into aqueous NH4Cl and extracted with Et2O. The combined extracts were dried over Na2SO4, filtered, and evaporated in vacuo. The product was used in the next step without further purification. Yield 0.39 g (93%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.04 min. MS (ESI) m / z 292.3 [M−H]+. 1 H-NMR (400MHz, CDCl3): δ (ppm) 1.18-1.48(m, 5H), 1.50-1.64 (m,4H), 1.82-2.03(m,2H), 2.27-2.48 (m, 6H), 2.62-2.78(m, 2H), 3.84-3.98(m, 2H), 3.92(q, 2H), 4.56(s, 1H), 5.31(s, 1H), 6.21(d, 1H), 7.44(d, 1H).

[0389] Synthesis of INT-26, ((2E,2'E)-2,2'-(1-(5-(3-(piperidin-1-yl)propyl)furan-2-yl)propane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide)) [ka] 2-Ethoxy-1-(5-(3-(piperidin-1-yl)propyl)furan-2-yl)prop-2-en-1-one (0.41 g, 1.45 mmol, 1 equiv.) was dissolved in EtOH (10 ml), and ethyl thiosemicarbazide (0.33 g, 2 equiv.) and 1 drop of H2SO4 were added. The reaction mixture was stirred and heated to reflux for 4 h, then maintained at ambient temperature for 15 h. The precipitate formed was filtered, washed with EtOH, water, Et2O, and crystallized from EtOH. Yield 0.08 g (12%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.21 min). MS (ESI) m / z 466.5 [M−H]+. 1 H-NMR (400MHz, CDCl3): δ (ppm) 1.11(t, 3H), 1.16(t, 1H), 1.53-1.91(m, 6H), 2.05-2.15(m, 2H), 2.32(s, 3H), 2.77-2.89(m, 2H), 3.05-3.19(m, 2H), 3.35-3.45(m, 4H), 3.53(q, 2H), 3.62(q, 2H), 6.49(s, 1H), 7.05(s, 1H), 7.78(s, 1H), 8.72(s, 1H), 10.48(s, 1H), 10.52(s, 1H).

[0390] Synthesis of INT-28, ((2Z,2'E)-2,2'-(1-(5-(3-morpholinopropyl)furan-2-yl)butane-2,3-diylidene)bis(N-ethylhydrazine-1-carbothioamide)): [ka] INT-28 was made using a procedure similar to that for preparing INT-26. Yield 0.18 g (50%). LCMS (C18 column 20 x 2 mm, 2.5 μm particle size, 100 A pore size, water-acetonitrile + 0.1% TFA, 3 min gradient from 5 to 87%, retention time 1.15 min). MS (ESI) m / z 468.5 [M-H]+. 1 H-NMR (400MHz, CDCl3): δ (ppm) 1.11(t, 3H), 1.16(t, 1H), 2.04-2.14(m, 2H), 2.32(s, 3H), 2.77-2.86(m, 2H), 3.17-3.26(m, 2H), 3.39-3.73(m, 10H), 3.91-4.04(m, 2H), 6.5(s, 1H), 7.06(s, 1H), 7.8(s, 1H), 8.72(s, 1H), 10.47(s, 1H), 10.52(s, 1H).

[0391] Synthesis of compound 26: [ka] CuCl2·2H2O (0.026 g, 1 equiv.) was added to thiosemicarbazone 6 (0.07 g, 0.15 mmol, 1 equiv.) in ethanol. The mixture was stirred at ambient temperature for 15 h. The formed complex precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum. Yield 0.054 g (68%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.76 min). MS (ESI) m / z 527.5 [M−H]+.

[0392] Synthesis of compound 28: [ka] The title compound was prepared from INT-28 according to the procedure for preparing compound 26. The product precipitated from the reaction mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum. Yield 0.14 g (85%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.65 min). MS (ESI) m / z 529.0 [M−H]+.

[0393] Scheme 13: Synthesis of compound 29 [ka] Synthesis of ethyl 5-(morpholinomethyl)furan-2-carboxylate: [ka] To a stirred solution of ethyl 2-chloromethyl-5-furoate (9.6 g, 50 mmol) in CHCl (200 mL) was added morpholine (4.43 g, 4.4 mL, 1 equiv.), triethylamine (10.3 g, 14 mL, 2 equiv.), and KI (0.1 g). The reaction mixture was stirred at room temperature for 15 h and then washed with water (3 × 50 mL). The organic layer was separated, dried over NaSO, filtered, and the solvent was evaporated. Yield 8 g (66%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 0.82 min). MS (ESI) m / z 240.1 [MH]. 1 H-NMR (400MHz, CDCl3): δ (ppm) 1.38 (t, 3H), 2.50-2.55 (m, 4H), 3.62 (s, 3H), 3.70-3.75 (m, 4H), 4.37 (q, 2H), 6.36 (d, 1H), 7.13 (d, 1H).

[0394] Synthesis of 5-(morpholinomethyl)furan-2-carboxylic acid hydrochloride: [ka] To a solution of ethyl 5-(morpholinomethyl)furan-2-carboxylate (4.6 g, 20 mmol) in methanol (100 ml) was added a solution of NaOH (2 g, 2 equivalents) in water (10 ml), and the reaction mixture was stirred at ambient temperature for 15 hours. The methanol was evaporated in vacuo, and the residue was diluted with water and acidified to pH 1. The acidified solution was evaporated to dryness, and the residue was treated with isopropanol. The solid salt was filtered, and the filtrate was evaporated to dryness. Yield 4.4 g (86%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile with 0.1% TFA, gradient 5 to 87% in 3 minutes, retention time 0.29 minutes). MS (ESI) m / z 212.3 [MH]+.

[0395] Synthesis of N-methoxy-N-methyl-5-(morpholinomethyl)furan-2-carboxamide: [ka] A mixture of 5-(morpholinomethyl)furan-2-carboxylic acid hydrochloride (7.1 g, 29 mmol) and 1,1'-carbonyldiimidazole (5.57 g, 1.2 equiv.) in DMF (47 mL) was stirred at 60 °C for 30 min. N,O-dimethylhydroxylamine (3.35 g, 1.2 equiv.) and triethylamine (3.2 g, 4.4 mL, 1.1 equiv.) were then added. The mixture was stirred at 80 °C for 16 h, then the volatiles were evaporated in vacuo and the residue was partitioned between EtOAc and HO. The organic layer was separated, dried over NaSO, filtered, and the solvent was evaporated. Yield 7 g (96%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 0.28 min. MS (ESI) m / z 255.6 [M−H]+, retention time 0.78 min. MS (ESI) m / z 255.6 [M−H]+. 1H-NMR (400MHz, CDCl3): δ (ppm) 2.52-2.55 (m, 4H), 3.35 (s, 3H), 3.64 (s, 2H), 3.71-3.74 (m, 4H), 6.36 (d, 1H), 6.71 (d, 1H).

[0396] Synthesis of 1-(5-(morpholinomethyl)furan-2-yl)ethan-1-one: [ka] A solution of N-methoxy-N-methyl-5-(morpholinomethyl)furan-2-carboxamide (3.4 g, 13 mmol, 1 equiv.) in THF (150 ml) was cooled to 5° C., and a solution of methylmagnesium bromide in THF (1.4 M, 26 ml, 3 equiv.) was added. The reaction mixture was stirred at 5° C. for 2 hours, poured into aqueous NH4Cl, and extracted with Et2O. The combined extracts were dried over Na2SO4, filtered, and the solvent was evaporated. Compound 3 was used in the next step without further purification. Yield 2.6 g (93%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 0.31 min, MS (ESI) m / z 210.1 [MH]+, retention time 0.67 min, MS (ESI) m / z 210.3 [MH]+). 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 2.34-2.45 (m, 7H), 3.49-3.63 (m, 6H), 6.54 (s, 1H), 7.46 (s, 1H).

[0397] Synthesis of INT-29, ((2E,2'E)-2,2'-(1-(5-(morpholinomethyl)furan-2-yl)ethane-1,2-diylidene)bis(N-methylhydrazine-1-carbothioamide)) [ka] A mixture of 1-(5-(morpholinomethyl)furan-2-yl)ethan-1-one (1.4 g, 7.0 mmol, 1 equiv.), NaBr (0.33 g, 0.5 equiv.), and DMSO (3.45 mL) was heated to 85 °C, and then H2SO4 (6 drops) was added (foaming), causing the reaction temperature to begin to rise. The reaction was heated to 110–115 °C, until the formation of dimethyl sulfide ceased and the reaction mixture became viscous. The viscous material that formed was dissolved in EtOH, and to this solution was added methyl thiosemicarbazide (1.41 g, 2 equiv.). The reaction mixture was refluxed for 2 h, then cooled to room temperature. The solvent was evaporated in vacuo, and the residue was dissolved in water (25 mL), neutralized with saturated aqueous Na2CO3, and extracted with EtOAc (3 × 50 mL). The organic layer was separated, dried over Na2SO4, filtered, and the solvent was evaporated. The residue was treated with water. The precipitate formed was filtered and washed with EtOH to give the pure title compound. Yield 0.7 g (26%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.08 min, MS (ESI) m / z 398.3 [M−H]+).

[0398] Synthesis of INT-38, ((2E,2'E)-2,2'-(1-(5-(morpholinomethyl)furan-2-yl)ethane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide)) [ka] INT-38 was made using a procedure similar to that for preparing INT-29. Yield: 0.5 g (37%). LCMS (C18 column 20 x 2 mm, 2.5 μm particle size, 100 A pore size, water-acetonitrile + 0.1% TFA, 3 min gradient from 5 to 87%, retention time 1.12 min, MS (ESI) m / z 426.0 [M-H]+).

[0399] Synthesis of compound 29: [ka] CuCl2·2H2O (0.062 g, 1 equiv.) was added to thiosemicarbazone 6 (0.14 g, 0.4 mmol, 1 equiv.) in ethanol. The mixture was stirred at ambient temperature for 15 h. The formed complex precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum. Yield: 0.055 g (32%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.29 min). MS (ESI) m / z 459.5 [M−H]+.

[0400] Synthesis of compound 38: [ka] The title compound was prepared from INT-36 according to the procedure for preparing compound 29. The product precipitated from the reaction mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum. Yield 0.07 g (77%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.47 min). MS (ESI) m / z 487.4 [M−H]+.

[0401] Scheme 14: Synthesis of compound 30 [ka] Synthesis of 5-(morpholine-4-carbonyl)furan-2-carboxylic acid: [ka] To a stirred solution of furan 2,5-dicarboxylic acid (5 g, 32 mmol, 1 equiv.) in DMF (100 ml), DIPEA was added (14.5 g, 19.5 ml, 3.5 equiv.), the reaction flask was flushed with argon, and a solution of TBTU (12.3 g, 1.2 equiv.) in DMF (75 ml) was added dropwise over 1 h at ambient temperature. The reaction mixture was stirred for an additional 1 h. Morpholine was then added in one portion, and the mixture was stirred at ambient temperature for 2 h. The mixture was cooled in an ice bath, HCl (2N, 170 ml) was added, and the product was extracted with EtOAc. The EtOAc was evaporated, and the residue was washed with EtOH and ether. Yield 6.19 g (85%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile with 0.1% TFA, gradient 5 to 87% in 3 min, retention time 0.33 min). MS (ESI) m / z 226.3 [MH]+, retention time 0.84 min). MS (ESI) m / z 226.3 [MH]+. 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 3.52-3.88(m, 8H), 7.09 (d, 1H), 7.29(d, 1H).

[0402] Synthesis of N-methoxy-N-methyl-5-(morpholine-4-carbonyl)furan-2-carboxamide: [ka] To a mixture of 5-(morpholine-4-carbonyl)furan-2-carboxylic acid (2.6 g, 11 mmol, 1 equiv.), N,O-dimethylhydroxylamine (1.46 g, 1.3 equiv.), HOBT (1.71, 1 equiv.), and DIPEA (2 ml) in DCM (150 ml) was added EDCI (2.21 g, 1 equiv.) at 4° C., and the mixture was stirred at room temperature overnight. The reaction mixture was treated with water. The solid material insoluble in water and DCM was removed by filtration. The organic layer was separated, dried over NaSO, filtered, and the solvent was evaporated. The residue was purified by column chromatography (SiO, CHCl 100%). Yield 2.1 g (68%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 0.95 min). MS (ESI) m / z 269.5 [M−H]+. 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 3.26 (s, 3H), 3.54-3.73 (m, 8H), 3.76 (s, 3H), 7.10 (d, 1H), 7.22 (d, 1H).

[0403] Synthesis of 1-(5-(morpholine-4-carbonyl)furan-2-yl)ethan-1-one: [ka] A solution of N-methoxy-N-methyl-5-(morpholine-4-carbonyl)furan-2-carboxamide (1.45 g, 5.4 mmol, 1 equiv.) in THF (50 ml) was cooled to 5 °C, and a solution of methylmagnesium bromide in THF (1.4 M, 11 ml, 3 equiv.) was added. The reaction mixture was stirred at 5 °C for 2 h, poured into aqueous NH4Cl, and extracted with Et2O. The combined extracts were dried over Na2SO4, filtered, and the solvent was evaporated. The title product was used in the next step without further purification. Yield 0.45 g (37%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile with 0.1% TFA, gradient 5 to 87% in 3 min, retention time 0.92 min). MS (ESI) m / z 224.4 [MH]+.1 H-NMR (400MHz, DMSO-d6): δ (ppm) 2.46 (s, 3H), 3.57-3.79 (m, 8H), 3.76 (s, 3H), 7.14 (d, 1H), 7.50 (d, 1H).

[0404] Synthesis of 2-(5-(morpholine-4-carbonyl)furan-2-yl)-2-oxoacetaldehyde: [ka] A three-neck flask was charged with SeO2 (0.42 g, 1.4 equiv.), 1,4-dioxane (6 mL), and water (0.36 mL). The mixture was heated to 50 °C and stirred until most of the SeO2 was dissolved. 1-(5-(morpholine-4-carbonyl)furan-2-yl)ethan-1-one (0.6 g, 0.003 M, 1 equiv.) was added, and the reaction was heated at gentle reflux overnight. Selenium solids precipitated during the course of the reaction. The mixture was cooled in an ice bath and filtered through diatomaceous earth to remove selenium. The filter cake was washed with portions of 1,4-dioxane. The filtrate was concentrated to give 0.5 g of crude title product, which was used in the next step without further purification. Yield 0.5 g (78%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 0.92 min, MS (ESI) m / z 238.1 [M−H]+).

[0405] Synthesis of INT-30, ((2E,2'E)-2,2'-(1-(5-(morpholine-4-carbonyl)furan-2-yl)ethane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide)): [ka] Crude 2-(5-(morpholine-4-carbonyl)furan-2-yl)-2-oxoacetaldehyde (0.5 g, 2.0 mmol, 1 equiv.) was dissolved in EtOH (25 ml), and ethyl thiosemicarbazide (0.5 g, 2 equiv.) and 2 drops of H2SO4 were added. The reaction mixture was stirred and heated to reflux for 4 h, then maintained at ambient temperature for 15 h. The precipitate formed was filtered, washed with EtOH, MeCN, water, Et2O, and dried. Yield 0.25 g (27%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.37 min, MS (ESI) m / z 440.5 [M-H]+). 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 1.00-1.26 (m, 6H), 3.43-4.09 (m, 13H), 7.19 (s, 1H), 7.24 (s, 1H), 6.06 (br.s, 1H), 8.92 (br.s, 1H), 11.98 (s, 1H), 12.29 (s, 1H).

[0406] Synthesis of intermediate ZN-30: [ka] Zn(OAc)2H2O (0.19 g, 1.5 equiv.) was added to INT-30 (0.73 g, 2.0 mmol, 1 equiv.) in ethanol. The mixture was refluxed for 4 h. The formed complex precipitated from the mixture as a yellow powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried in vacuo. Yield 0.175 g (61%). 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 1.11(t, 3H), 1.19 (t, 3H), 3.36-3.85 (m, 13H), 7.11 (s, 1H), 7.15 (s, 1H), 8.20 (s, 1H), 8.43 (s, 1H).

[0407] Synthesis of compound 30: [ka] ZN-30 (0.175 g, 0.3 mmol, 1 equiv.) was dissolved in DMSO (4 mL) and a solution of CuCl2H2O (0.076 g, 1.1 equiv.) in water (4 mL) was added. The mixture was stirred for 5 min, filtered, and washed with water and Et2O. Yield 0.08 g (46%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.86 min). MS (ESI) m / z 501.3 [M−H]+.

[0408] Scheme 15: Synthesis of compound 34 [ka] Synthesis of 2-(furan-2-yl)-2-oxoacetaldehyde: [ka] A three-neck flask was charged with SeO2 (3.2 g, 28.6 mmol), 1,4-dioxane (37 mL), and water (2.5 mL). The mixture was heated to 50 °C and stirred until most of the SeO2 was dissolved. 1-(2-Furyl)ethanone (3 g, 27.2 mmol) was added, and the reaction was heated at gentle reflux overnight. The reaction progress was monitored by TLC (CCl4 / EtOAc 7:3). Selenium solids precipitated during the course of the reaction. The mixture was cooled in an ice bath and filtered through diatomaceous earth to remove the selenium. The filter cake was washed with portions of 1,4-dioxane. The filtrate was concentrated to give 3.0 g of crude compound 1, which was used in the next step without further purification. Yield 3.0 g (88%).

[0409] Synthesis of INT-34, ((2Z,2'E)-2,2'-(1-(furan-2-yl)ethane-1,2-diylidene)bis(N-methylhydrazine-1-carbothioamide)): [ka] 2-(Furan-2-yl)-2-oxoacetaldehyde (0.7 g, 6 mmol) was dissolved in EtOH (20 mL), and methyl thiosemicarbazide (1.3 g, 12 mmol) and 3 drops of H2SO4 were added. The reaction mixture was stirred and heated to reflux for 4 h, then maintained at ambient temperature for 15 h. The reaction progress was monitored by TLC (CCl4 / EtOAc 7:3). The precipitate formed was filtered, washed with EtOH, water, Et2O, and dried. Yield 0.57 g (32%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile with 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.35 min). MS (ESI) m / z 299.5 [MH]+. 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 3.02 (d, 3H), 3.01 (d, 3H), 6.78 (q, 1H), 7.52 (d, 1H), 7.84 (s, 1H), 7.99-8.04 (m, 1H), 8.13 (dd, 1H), 8.88-8.92 (m, 1H), 10.81 (s, 1H), 11.79 (s,1H).

[0410] Synthesis of INT-35, ((2Z,2'E)-2,2'-(1-(furan-2-yl)ethane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide)) [ka] INT-35 was made using a procedure similar to that for preparing INT-34. Yield: 0.47 g (24%). LCMS (C18 column 20 x 2 mm, 2.5 μm particle size, 100 A pore size, water-acetonitrile + 0.1% TFA, 3 min gradient from 5 to 87%, retention time 2.23 min). MS (ESI) m / z 327.5 [M−H]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 1.07 (t, 3H), 1.15 (t, 3H), 3.41-3.48 (m, 2H), 3.55-3.63 (m, 2H), 6.78 (q, 1H), 7.52 (d, 1H), 7.84 (s, 1H), 7.99-8.04 (m, 1H), 8.13 (dd, 1H), 8.88-8.92 (m, 1H), 10.81 (s, 1H), 11.79 (s,1H).

[0411] Synthesis of INT-36, ((2Z,2'E)-2,2'-(1-(5-nitrofuran-2-yl)ethane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide)): [ka] INT-36 was made using a procedure similar to that for preparing INT-34. Yield: 0.02 g (24%). LCMS (C18 column 20 x 2 mm, 2.5 μm particle size, 100 A pore size, water-acetonitrile + 0.1% TFA, 10 min gradient from 5 to 87%, retention time 8.11 min). MS (ESI) m / z 372.5 [M−H]+.

[0412] Synthesis of INT-40, ((2Z,2'E)-2,2'-(1-(5-bromothiophen-2-yl)ethane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide)): [ka] INT-40 was made using a procedure similar to that for preparing INT-34. Yield 0.24 g (39%). LCMS (C18 column 20 x 2 mm, 2.5 μm particle size, 100 A pore size, water-acetonitrile + 0.1% TFA, 3 min gradient from 5 to 87%, retention time 1.85 min). MS (ESI) m / z 422.4 [M−H]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 1.15 (t, 3H), 1.18 (t, 3H), 3.41-3.49 (m, 4H), 7.25 (d, 1H), 7.33 (d, 1H), 8.09 (t, 1H), 8.16 (s, 1H), 8.60 (t, 1H), 11.75 (s, 1H), 11.90 (s,1H).

[0413] Synthesis of compound 34: [ka] CuCl2·2H2O (0.33 g, 1.9 mmol) was added to INT-34 (0.57 g, 1.9 mmol) in 10 ml of ethanol. The mixture was stirred overnight. The complex was isolated as a reddish-brown powder. After cooling, the formed precipitate was collected by filtration, washed with water (2 × 50 ml), ethanol (2 × 50 ml), and copious amounts of diethyl ether (5 × 50 ml), and then dried under vacuum. Yield: 0.3 g (47%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile with 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.40 min). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.83 min). MS (ESI) m / z 360.3 [MH]+.

[0414] Synthesis of compound 35: [ka] The title compound was prepared from INT-35 according to the procedure for preparing compound 34. After cooling, the product was collected by filtration, washed with water (2 x 50 ml), ethanol (2 x 50 ml), and copious amounts of diethyl ether (5 x 50 ml), and then dried under vacuum. Yield 0.3 g (57%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 2.18 min). MS (ESI) m / z 388.5 [M−H]+.

[0415] Synthesis of compound 36: [ka] The title compound was prepared from INT-36 according to the procedure for preparing compound 34. The product was isolated as a reddish-brown powder. Yield 0.026 g (40%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.70 min). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.69 min). MS (ESI) m / z 433.2 [M−H]+.

[0416] Synthesis of compound 40: [ka] The title compound was prepared from INT-40 according to the method for preparing compound 34. The product was isolated as a reddish-brown powder. After cooling, the precipitate formed was collected by filtration, washed with water (2 x 50 ml), ethanol (2 x 50 ml), and a large amount of diethyl ether (5 x 50 ml), and then dried under vacuum. Yield 0.01 g (6%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 2.72 min). MS (ESI) m / z 484.1 [M−H]+.

[0417] Scheme 16: Synthesis of compound 42 [ka] Synthesis of 1-(4-(phenylsulfonyl)morpholin-2-yl)ethan-1-one: [ka] To a solution of 1-morpholin-2-yl-ethanone (0.3 g, 2.3 mmol) in DCM (50 ml) was added triethylamine (0.59 g, 2.5 equiv.) at 5° C., followed by benzenesulfonyl chloride (0.51 g, 1.25 equiv.). The mixture was stirred at ambient temperature for 15 h, acidified with 10% aqueous HCl, and extracted with DCM. The combined organic extracts were dried over Na2SO4, filtered, and evaporated. The residue was purified by column chromatography (silica gel, eluent 10% EtOAc in hexane). Yield 0.30 g (48%). NMR (400MHz, CDCl3): 2.20 (s, 3H), 2.22-2.28 (m, 1H), 2.46 (ddd, 1H), 3.58-3.61 (m, 1H), 3.76 (ddd, 1H), 3.90-3.95 (m, 1H), 4.00-4.09 (m, 2H), 7.54-7.60 (m, 2H), 7.63-7.67 (m, 1H), 7.77-7.80 (m, 2H).

[0418] Synthesis of INT-42, ((2Z,2'Z)-2,2'-(1-(4-(phenylsulfonyl)morpholin-2-yl)ethane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide)) [ka] A flask was charged with SeO2 (0.14 g, 1.1 equiv.), 1,4-dioxane (3.5 mL), and water (0.1 mL). The mixture was warmed to 50 °C and stirred until most of the SeO2 was dissolved. 1-(4-(phenylsulfonyl)morpholin-2-yl)ethan-1-one was added, and the reaction was heated at gentle reflux for 4 hours. Selenium solids precipitated over the course of the reaction. The mixture was cooled in an ice bath and filtered through diatomaceous earth to remove the selenium. The filter cake was washed with portions of 1,4-dioxane. The filtrate was concentrated in vacuo until most of the 1,4-dioxane was removed. The residue was dissolved in EtOH and filtered. To the filtrate was added thiosemicarbazide and one drop of H2SO4, and the reaction mixture was refluxed for 2 hours. The precipitate was filtered. Yield 0.08 g (15%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.62 min), MS (ESI) m / z 486.5 [MH]+.

[0419] Synthesis of compound 42: [ka] INT-42 (0.08 g, 0.17 mmol) was dissolved in DMSO (0.4 mL) and a solution of CuCl 2H O (28 mg, 1.0 equiv.) in water (0.4 mL) was added. The mixture was stirred for 5 min, filtered, and the precipitate was washed with a saturated solution of potassium carbonate, water, and Et O. Yield: 0.015 g (17%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 2.27 min). MS (ESI) m / z 547.5 [M−H].

[0420] Scheme 17: Synthesis of compound 43 [ka] Synthesis of methyl morpholine-2-carboxylate hydrochloride: [ka] To a suspension of morpholine-2-carboxylic acid (1.94 g, 15 mmol, 1 equiv.) in methanol (75 mL) was added thionyl chloride (8.8 g, 5.4 mL, 5 equiv.) dropwise at 0-10 °C. The reaction mixture was stirred at room temperature for 1 h and then heated to reflux for 4 h. The reaction mixture was evaporated. Yield 2.3 g (85.6%). NMR (400 MHz, DMSO-d6): 2.78-3.15 (m, 3H), 3.25-3.35 (m, 1H), 3.69 (s, 3H), 3.69-3.81 (m, 1H), 3.95-4.05 (m, 1H), 4.60 (dd, 1H), 9.80-10.40 (m, 2H).

[0421] Synthesis of methyl 4-(methylsulfonyl)morpholine-2-carboxylate: [ka] A mixture of methyl morpholine-2-carboxylate hydrochloride (2.3 g, 12.7 mmol, 1 equiv.), methanesulfonyl chloride (1.74 g, 1.1 mL, 1.2 equiv.), and triethylamine (3.2 g, 4.4 mL, 2.5 equiv.) in methylene chloride (100 mL) was stirred at ambient temperature for 15 hours. The reaction mixture was washed with water, dried over Na2SO4, filtered, and the solvent was evaporated. Yield 1.3 g (46%). NMR (400MHz, CDCl3): 2.83 (s, 3H), 2.95-3.04 (m, 2H), 3.50-3.58 (m, 1H), 3.74-3.80 (m, 1H), 3.82 (s, 3H), 3.83-3.88 (m, 1H), 4.09 (ddd, 1H), 4.27 (dd, 1H).

[0422] Synthesis of 4-(methylsulfonyl)morpholine-2-carboxylic acid: [ka] Methyl 4-(methylsulfonyl)morpholine-2-carboxylate (1.3 g, 5.8 mmol, 1 equiv.) was dissolved in methanol (50 mL) and a solution of NaOH (0.58 g, 2.5 equiv.) in water (10 mL) was added. The reaction mixture was stirred overnight at room temperature. Methanol was removed in vacuo, and the residue was diluted with water, acidified to pH 1 with concentrated HCl, and extracted with EtOAc. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo. Yield 0.95 g (78%). NMR (400 MHz, DMSO-d6): 2.32 (s, 3H), 2.87-2.95 (m, 1H), 3.20-3.25 (m, 2H), 3.51-3.59 (m, 2H), 3.83-3.99 (m, 2H).

[0423] Synthesis of N-methoxy-N-methyl-4-(methylsulfonyl)morpholine-2-carboxamide: [ka] To a stirred solution of 4-(methylsulfonyl)morpholine-2-carboxylic acid (0.97 g, 5 mmol, 1 equiv.) in THF (25 ml) at 0°C, carbonyldiimidazole (0.69 g, 0.5 equiv.) was added. N,O-dimethylhydroxylamine hydrochloride (0.45 g, 1 equiv.) and triethylamine (2.34 g, 3.2 ml, 5 equiv.) were then added to the solution, and the ice bath was removed. The reaction mixture was stirred at room temperature until the disappearance of the acid, as determined by TLC. Upon completion, triethylamine hydrochloride was removed by filtration. The filtrate was concentrated to dryness via rotary evaporation. The residue was purified by short-path silica gel column chromatography, eluting with 20% ethyl acetate in hexane. Yield 0.26 g (22%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 0.99 min), MS (ESI) m / z 253.1 [MH]+.

[0424] Synthesis of 2-ethoxy-1-(4-(methylsulfonyl)morpholin-2-yl)prop-2-en-1-one: [ka] A solution of ethyl vinyl ether (0.82 g, 1 ml, 11 equiv.) in anhydrous tetrahydrofuran (20 mL) was cooled to -78 °C, and tert-butyllithium in pentane (1.7 M, 6 ml, 9.9 equiv.) was added. The mixture was warmed to 0 °C over a 1-hour period, stirred for 45 minutes, and then cooled to -30 °C. Magnesium bromide etherate (2.5 g, 9.9 equiv.) was added. The mixture was then warmed to 0 °C over a 15-minute period, and N-methoxy-N-methyl-4-(methylsulfonyl)morpholine-2-carboxamide (0.26 g, 1 mmol, 1 equiv.) in THF was added. The mixture was stirred at 0 °C for 4 hours. The progress of the reaction was monitored by TLC. The mixture was poured into aqueous NH Cl and extracted with Et O. The combined extracts were dried over Na SO , filtered, and the solvent was evaporated. The product was used in the next step without further purification. Yield 0.17 g (62%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.36 min), MS (ESI) m / z 527.3 [2MH]+

[0425] Synthesis of INT-43, ((2Z,2'Z)-2,2'-(1-(4-(methylsulfonyl)morpholin-2-yl)propane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide)): [ka] 2-Ethoxy-1-(4-(methylsulfonyl)morpholin-2-yl)prop-2-en-1-one (0.16 g, 0.6 mmol, 1 equiv.) was dissolved in EtOH (20 ml), and ethyl thiosemicarbazide (0.14 g, 2 equiv.) and 1 drop of H2SO4 were added. The reaction mixture was stirred and heated to reflux for 4 h, then maintained at ambient temperature for 15 h. The formed precipitate was filtered, washed with EtOH, water, Et2O, and dried. Yield 0.15 g (55%). NMR (400MHz, DMSO-d6): 1.10-1.21 (m, 6H), 1.47-1.53 ​​(m, 1H), 2.16-2.21 (m, 1H), 2.47-2.55 (m, 4H), 2.78-2.84 (m, 1H), 2.95 (br.d, 1H), 3.08-3.16 (m, 1H), 3.30 (s, 3H), 3.42-3.50 (m, 4H), 7.78 (br.s, 1H), 8.69 (br.s, 1H), 10.75 (s, 1H), 12.18 (s, 1H). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.47 min), MS (ESI) m / z 438.4 [M−H]+.

[0426] Synthesis of compound 43: [ka] CuCl2·2H2O (0.058 g, 1 equiv.) was added to thiosemacarbazone 6 (0.15 g, 0.3 mmol, 1 equiv.) in ethanol. The mixture was stirred at ambient temperature for 15 h. The formed complex precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum. Yield: 0.07 g (41%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 2.06 min). MS (ESI) m / z 499.5 [M−H]+.

[0427] Scheme 18: Synthesis of compound 44 [ka] Synthesis of 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid: [ka] Morpholine-2-carboxylic acid (2 g, 15.6 mmol) was dissolved in a mixture of dioxane and water (8 ml / 4 ml), then potassium carbonate (4.3 g, 2 eq.) was added, and the mixture was stirred for 30 minutes. Di-tert-butyl dicarbonate (3.7 g, 1.1 eq.) was added, the reaction mixture was stirred overnight, the solvent was evaporated, the residue was dissolved in water, the solution was acidified with 10% H2SO4, and the product was extracted with EtOAc. The organic layer was separated, dried over Na2SO4, filtered, and the solvent was evaporated. Yield 1.7 g (47%). NMR (400MHz, DMSO-d6): 1.40 (s, 9H), 3.04-3.10 (m, 2H), 3.42-3.56 (m, 2H), 3.78-3.84 (m, 2H), 4.01-4.07 (m, 1H), 12.95 (br.s, 1H).

[0428] Synthesis of tert-butyl 2-(methoxy(methyl)carbamoyl)morpholine-4-carboxylate: [ka] A solution of CDI (7 ml) in THF was added to a solution of 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (7 ml) in THF at 0° C. The mixture was stirred at room temperature for 1 h. The mixture was then cooled to 0° C., and a suspension of triethylamine (0.7 ml) and N,O-dimethylhydroxylamine in MeCN (10 ml) was added at 0° C., and the reaction was stirred at room temperature for 16 h. The solvent was then evaporated, the residue was dissolved in DCM, and the solution was washed with water, acetic acid (20% solution), and saturated NaHCO3. The organic layer was separated and dried. The organic layer was washed with water, separated, dried over Na2SO4, filtered, and the solvent was evaporated. The residue was purified by column chromatography (SiO2 / hexane:EtOAc 2:1). Yield 0.78 g (73%). NMR (400MHz, CDCl3): 1.49 (s, 9H), 3.02 (br.s, 1H), 3.24 (s, 3H), 3.60 (dd, 1H), 3.75 (s, 3H), 3.90 (br.s, 1H), 4.00-4.30 (m, 2H), 4.85 (br.s, 1H).

[0429] Synthesis of tert-butyl 2-(2-ethoxyacryloyl)morpholine-4-carboxylate: [ka] A solution of ethyl vinyl ether (2 g, 2.6 ml, 11 equiv.) in anhydrous tetrahydrofuran (75 mL) was cooled to −78° C., and tert-butyllithium in pentane (1.7 M, 13 ml, 8.9 equiv.) was added. The mixture was warmed to 0° C. over a 1-hour period, stirred for 45 minutes, and then cooled to −30° C. Magnesium bromide etherate (5.2 g, 8.9 equiv.) was added. The mixture was then warmed to 0° C. over a 15-minute period, and tert-butyl 2-(methoxy(methyl)carbamoyl)morpholine-4-carboxylate (0.7 g, 2.6 mmol, 1 equiv.) in THF was added. The mixture was stirred at 0° C. for 4 hours. The progress of the reaction was monitored by TLC. The mixture was poured into aqueous NH4Cl and extracted with Et2O. The combined extracts were dried over Na2SO4 and evaporated. The product was used in the next step without further purification. Yield 0.6 g (82%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.33 min), MS (ESI) m / z 286.1 [MH]+.

[0430] Synthesis of tert-butyl 2-((6E,8E)-8-methyl-4,11-dithioxo-3,5,6,9,10,12-hexaazatetradeca-6,8-dien-7-yl)morpholine-4-carboxylate: [ka] tert-Butyl 2-(2-ethoxyacryloyl)morpholine-4-carboxylate (0.39 g, 1.4 mmol, 1 equiv.) was dissolved in EtOH (150 ml), and ethyl thiosemicarbazide (0.33 g, 2 equiv.) and 3 drops of H2SO4 were added. The reaction mixture was stirred and heated to reflux for 4 h, then maintained at ambient temperature for 15 h. The formed precipitate was filtered, washed with EtOH, water, Et2O, and dried. Yield 0.23 g (37.2%). NMR (400MHz, DMSO-d6): 1.10-1.18 (m, 6H), 1.40 (br.d, 9H), 2.20 (s, 3H), 2.90-2.06 (m, 1H), 3.18 (br.s, 1H), 3.52-3.80 (m, 6H), 3.82-3.87 (m, 1H), 4.02-4.07 (m, 2H), 5.12 (br.s, 1H), 8.28 (br.s, 1H), 8.51 (t, 1H), 10.24 (s, 1H), 11.20 (br.s, 1H).

[0431] Synthesis of INT-44, (2E,2'E)-2,2'-(1-(morpholin-2-yl)propane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide) hydrochloride: [ka] To a solution of tert-butyl 2-((6E,8E)-8-methyl-4,11-dithioxo-3,5,6,9,10,12-hexaazatetradeca-6,8-dien-7-yl)morpholine-4-carboxylate (0.23 g, 0.5 mmol) in dioxane, HCl / dioxane (3 M, 6 ml) was added. The reaction mixture was stirred overnight at room temperature. The precipitate formed was filtered. Yield 0.15 g (76%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.13 min), MS (ESI) m / z 360.4 [MH]+.

[0432] Synthesis of compound 44: [ka] CuCl2·2H2O (0.036 g, 1 equiv.) was added to INT-44 (0.1 g, 0.2 mmol, 1 equiv.) in ethanol. The mixture was stirred at ambient temperature for 15 h. The formed complex precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum. Yield: 0.03 g (33%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.47 min). MS (ESI) m / z 421.0 [M−H]+.

[0433] Scheme 19: Synthesis of compound 45 [ka] Synthesis of 4-benzylmorpholine-2-carbonitrile: [ka] 2-Chloroacetonitrile (6 g, 1.03 equiv.) was dissolved in toluene (16 ml). A solution of N-benzylethanolamine (10 g, 66 mmol) in toluene (5 ml) was added, and the reaction mixture was stirred at ambient temperature for 15 hours. Toluene (30 ml) was then added, and the solution was cooled to -5°C. A suspension of t-BuOK (7.6 g, 1.03 equiv.) in THF (128 ml) was slowly added, and the mixture was stirred at -5°C for 50 minutes. The mixture was washed with brine, dried, and evaporated. The residue was purified by column chromatography (silica gel, hexane:EtOAc, 3:1 to 1:1 gradient). Yield 8.4 g (62.8%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.22 min), MS (ESI) m / z 203.4 [MH]+.

[0434] Synthesis of 4-benzylmorpholine-2-carboxylic acid: [ka] 4-Benzylmorpholine-2-carbonitrile (1.6 g, 7.9 mmol, 1 equiv.) was dissolved in HCl (6 M, 65 ml) and the reaction mixture was refluxed for 2.5 h. Toluene (15 ml) was then added and refluxing continued for an additional 3 h. The reaction mixture was evaporated to dryness. Yield 1.6 g (78.5%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 0.65 min), MS (ESI) m / z 222.4 [M−H]+.

[0435] Synthesis of 4-benzyl-N-methoxy-N-methylmorpholine-2-carboxamide: [ka] A solution of CDI (1.2 g, 1.2 equiv.) in THF (12 ml) was added to a solution of 4-benzylmorpholine-2-carboxylic acid (1.6 g, 6.2 mmol, 1 equiv.) and triethylamine (0.8 ml) in THF (12 ml) at 0 °C. The mixture was stirred at room temperature for 1 h. The mixture was then cooled to 0 °C, and a suspension of triethylamine (1.2 ml) and N,O-dimethylhydroxylamine (0.73 g, 1.2 equiv.) in MeCN (17 ml) at 0 °C was added, and the reaction was stirred at room temperature for 16 h. The solvent was then evaporated. The residue was dissolved in DCM, and the solution was washed with water, followed by acetic acid (20% aqueous solution) and saturated aqueous NaHCO3. The organic layer was separated, dried over Na2SO4, filtered, and the solvent was evaporated. Yield 0.9 g (54.8%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.00 min), MS (ESI) m / z 265.1 [M−H]+.

[0436] Synthesis of 1-(4-benzylmorpholin-2-yl)-2-ethoxyprop-2-en-1-one: [ka] A solution of ethyl vinyl ether (0.34 g, 0.5 ml, 3.3 equiv.) in anhydrous tetrahydrofuran (20 mL) was cooled to −78° C., and tert-butyllithium in pentane (1.7 M, 2.4 ml, 3 equiv.) was added. The mixture was warmed to 0° C. over a 1-hour period, stirred for 45 minutes, and then cooled to −30° C. 4-Benzyl-N-methoxy-N-methylmorpholine-2-carboxamide (3.0 g, 7.5 mmol, 1 equiv.) was added in THF, and the mixture was stirred at 0° C. for 4 hours. The progress of the reaction was monitored by TLC. The mixture was poured into aqueous NH4Cl and extracted with Et2O. The combined extracts were dried over Na2SO4, filtered, and the solvent was evaporated. The product was used in the next step without further purification. Yield 0.3 g (82%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.03 min), MS (ESI) m / z 276.1 [MH]+.

[0437] Synthesis of INT-45, ((2E,2'E)-2,2'-(1-(4-benzylmorpholin-2-yl)propane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide): [ka] 1-(4-Benzylmorpholin-2-yl)-2-ethoxyprop-2-en-1-one (0.3 g, 1 mmol, 1 equiv.) was dissolved in EtOH (10 ml), and ethyl thiosemicarbazide (0.26 g, 2 equiv.) and 1 drop of H2SO4 were added. The reaction mixture was stirred and heated to reflux for 4 h, then maintained at ambient temperature for 15 h. The formed precipitate was filtered, washed with EtOH, water, Et2O, and dried. Yield 0.08 g (16%). NMR (400 MHz, DMSO-d6): 1.05 (t, 6H), 2.37 (s, 3H), 3.50-3.56 (m, 4H), 3.80 (br.s, 1H), 4.25 (br.s, 2H), 5.65 (br.s, 1H), 7.30-7.48 (m, 4H), 8.09 (br.s, 1H), 8.59 (br.s, 1H), 10.22 (s, 1H), 10.80 (br.s, 1H). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile with 0.1% TFA, gradient 5-87% in 3 min, retention time 1.20 min), MS (ESI) m / z 450.4 [MH]+.

[0438] Synthesis of compound 45: [ka] CuCl2·2H2O (0.017 g, 1 equiv.) was added to INT-45 (0.045 g, 0.1 mmol, 1 equiv.) in ethanol. The mixture was stirred at ambient temperature for 15 h. The formed complex precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum. Yield: 0.035 g (68.5%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.70 min). MS (ESI) m / z 511.3 [M−H]+.

[0439] Scheme 20: Synthesis of compound 46 [ka] Synthesis of benzyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate: [ka] To a mixture of 1-((benzyloxy)carbonyl)piperidine-4-carboxylic acid (21.2 g, 80.6 mmol), N,O-dimethylhydroxylamine (10.2 g, 96.7 mmol), HOBT (12.1 g, 96.7 mmol), and TEA (18.5 ml, 241.8 mmol) in DCM (300 ml) was added EDCI (17.1 g, 96.7 mmol) at 4 °C, and the mixture was stirred at ambient temperature for 15 h. The mixture was washed with water (50 ml), 1 N HCl (aq) (50 ml), water (100 ml), and brine (150 ml). The organic layer was dried over anhydrous NaSO and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent 100% DCM to 5% MeOH) to give crude 1. Yield 22.7 g (92%). NMR (400MHz, DMSO-d6): 1.36-1.43 (m, 2H), 1.64-1.70 (m, 2H), 2.84-2.98 (m, 2H), 3.09 (s, 3H), 3.68 (s, 3H), 4.00-4.06 (m, 2H), 5.07-s, 2H), 7.30-7.41 (m, 5H).

[0440] Synthesis of benzyl 4-(2-ethoxyacryloyl)piperidine-1-carboxylate: [ka] A solution of ethyl vinyl ether (2.0 g, 28.1 mmol) in anhydrous tetrahydrofuran (45 ml) was cooled to -78 °C, and tert-butyllithium in pentane (1.7 M, 15.6 ml, 25.5 mmol) was added. The mixture was warmed to 0 °C over a 1-hour period, stirred for 45 minutes, and then cooled to -30 °C. Benzyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (2.6 g, 8.5 mmol) was added in THF (15 ml) with stirring at 0 °C for 4 hours. The progress of the reaction was monitored by TLC. The mixture was poured into dilute NH Cl (100 ml) and extracted with Et O (3 × 100 ml). The combined extracts were dried over Na SO , filtered, and the solvent was evaporated. The product was used in the next step without further purification. Yield 0.77 g (29%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.58 min), MS (ESI) m / z 318.2 [MH]+.

[0441] Synthesis of benzyl 4-((6Z,8E)-8-methyl-4,11-dithioxo-3,5,6,9,10,12-hexaazatetradeca-6,8-dien-7-yl)piperidine-1-carboxylate: [ka] Benzyl 4-(2-ethoxyacryloyl)piperidine-1-carboxylate (1.5 g, 4.6 mmol) was dissolved in EtOH (80 ml), and ethyl thiosemicarbazide (1.2 g, 10.1 mmol) and 3 drops of H2SO4 were added. The reaction mixture was stirred and heated to reflux for 4 hours, then maintained at ambient temperature for 15 hours. The precipitate formed was filtered, washed with EtOH, water, Et2O, and dried. Yield: 0.3 g (14%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile with 0.1% TFA, gradient 5 to 87% in 3 minutes, retention time 1.47 minutes), MS (ESI) m / z 492.2 [M-H]+.

[0442] Synthesis of INT-46, ((2Z,2'E)-2,2'-(1-(piperidin-4-yl)propane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide)) [ka] Benzyl 4-((6Z,8E)-8-methyl-4,11-dithioxo-3,5,6,9,10,12-hexaazatetradeca-6,8-dien-7-yl)piperidine-1-carboxylate (0.35 g, 0.7 mmol) was dissolved in CF3COOH (5 ml) and the solution was heated to reflux for 2.5 h. After cooling to ambient temperature, the reaction mixture was diluted with saturated aqueous NaHCO3 and extracted with CHCl2 (3 x 15 ml). The organic layer was washed with water, separated, dried over Na2SO4, filtered, and the solvent was evaporated. The residue was purified by column chromatography (silica gel, eluent 100% DCM to 5% MeOH) to give the crude title product. Yield 0.25 g (98%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.11 min), MS (ESI) m / z 358.5 [M−H]+.

[0443] Synthesis of compound 46: [ka] Cu(OAc)2·2H2O (0.02 g, 0.09 mmol) was added to INT-46 (0.03 g, 0.08 mmol) in methanol. The mixture was stirred at ambient temperature for 15 h. The formed complex precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum. Yield: 0.04 g (90%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 2.85 min). MS (ESI) m / z 419.5 [M−H]+.

[0444] Example 3: Preparation of compounds 47-53 Scheme 21: Synthesis of compound 47 [ka] Synthesis of 2-(cyclopent-2-en-1-yl)ethan-1-ol: [ka] To a stirred suspension of LiAlH4 (3.76 g, 99.0 mmol, 2.5 equiv) in THF (250 ml) was slowly added a solution of cyclopent-2-eneacetic acid (5.0 g, 39.6 mmol, 1.0 equiv) in THF (50 ml) at 0 °C. The mixture was heated to reflux for 3 h and then cooled to 0 °C. The reaction was quenched with Na2SO4 (10%) and extracted with Et2O (3 × 100 ml). The combined extracts were dried over Na2SO4, filtered, and evaporated. The product was used in the next step without further purification. Yield 4.06 g (91%). 1 H-NMR (400MHz, CDCl3): δ (ppm) 1.40-1.48 (m, 1H), 1.50-1.51 (m, 1H), 1.56-1.64 (m, 1H), 1.67-1.76 (m, 1H), 2.04-2.13 (m, 1H), 2.27-2.37 (m, 2H), 2.78 (br.s, 1H), 3.66-3.75 (m, 2H), 5.68-5.71 (m, 1H), 5.74-5.76 (m, 1H).

[0445] Synthesis of tert-butyl(2-(cyclopent-2-en-1-yl)ethoxy)diphenylsilane: [ka] To a solution of 2-(cyclopent-2-en-1-yl)ethan-1-ol (4.05 g, 36.1 mmol) in dichloromethane (200 ml), tert-butyldiphenylsilyl chloride (11.9 g, 43.3 mmol), triethylamine (4.7 g, 46.9 mmol), and 4-(dimethylamino)pyridine (0.22 g, 1.8 mmol) were added, and the mixture was stirred at room temperature for 3 hours. After quenching the reaction with 1N hydrochloric acid, the mixture was extracted with dichloromethane. The organic extract was washed with water, aqueous sodium bicarbonate, and brine, dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo. Flash chromatography of the residue (silica gel, hexane-ethyl acetate 50:1) afforded compound 2. Yield: 11.3 g (89%). 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 0.99 (s, 9H), 1.26-1.35 (m, 1H), 1.43-1.51 (m, 1H), 1.61-1.69 (m, 1H), 1.88-1.97 (m, 1H), 2.13-2.30 (m, 2H), 2.70-2.76 (m, 1H), 3.68 (t, 2H), 5.62-5.65 (m, 1H), 5.66-5.70 (m, 1H), 7.41-7.46 (m, 6H), 7.60-7.62 (m, 4H).

[0446] Synthesis of 3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclopentane-1,2-diol: [ka] tert-Butyl(2-(cyclopent-2-en-1-yl)ethoxy)diphenylsilane (9.0 g, 25.6 mmol) was dissolved in a mixture of HO-tBuOH (1:3), followed by the addition of N-methylmorpholine N-oxide (3.9 g, 33.3 mmol) and OsO (0.004 g of a 4% aqueous solution, 0.001 equiv.). The reaction mixture was stirred at 60 °C until completion, as monitored by TLC (CHCl-CHOH, 20:1). The solid catalyst was filtered and rinsed with EtOAc, and the filtrate was quenched with an aqueous solution of NaSO (10%). The aqueous layer was extracted with EtOAc, and the combined organic extracts were dried over NaSO, filtered, and the solvent was evaporated. The crude product was purified by flash chromatography (CHCl-MeOH, 1:0 to 95:5 gradient) to give diol 3. Yield 6.3 g (64%). LCMS (C18 column 20 x 2 mm, 2.5 μm particle size, 100 A pore size, water-acetonitrile + 0.1% TFA, 3 min gradient 5 to 87%, retention time 1.99 min). MS (ESI) m / z 385.1 [M−H]+. 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 0.98 (s, 9H), 1.26-1.55 (m, 2H), 1.66-1.68 (m, 1H), 1.69-1.78 (m, 2H), 1.79-1.88 (m, 2H), 3.59-3.60 (m, 1H), 3.67 (q, 2H), 3.74-3.88 (m, 1H), 4.09 (dd, 1H), 4.32 (dd, 1H), 7.41-7.48 (m, 6H), 7.60-7.62 (m, 4H).

[0447] Synthesis of 3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclopentane-1,2-dione: [ka] Dimethyl sulfoxide (3.6 g, 46.8 mmol) was added to a stirred solution of oxalyl chloride (2.97 g, 23.4 mmol) in dichloromethane (100 ml) at −78° C. After 15 minutes, a solution of 3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclopentane-1,2-diol (3.0 g, 7.9 mmol) in dichloromethane (20 ml) was added slowly (over a 15 minute period), and the resulting solution was stirred at −78° C. for 1 hour. Triethylamine (7.3 g, 70 mmol) was then added, and the mixture was stirred at −78° C. for 15 minutes and then allowed to warm to ambient temperature. The reaction mixture was washed with water, and the organic layer was dried over NaSO, filtered, and evaporated. Yield 1.6 g (54%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 2.01 min). MS (ESI) m / z 381.1 [MH]+. 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 0.97 (s, 9H), 1.90 (t, 1H), 2.27-2.35 (m, 2H), 2.46-2.51 (m, 2H), 3.52-3.46 (m, 2H), 3.63-3.86 (m, 2H), 7.41-7.48 (m, 6H), 7.60-7.62 (m, 4H).

[0448] Synthesis of (2E,2'E)-2,2'-(3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclopentane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide): [ka] 3-(2-((tert-Butyldiphenylsilyl)oxy)ethyl)cyclopentane-1,2-dione (1.6 g, 4.2 mmol) was dissolved in EtOH (25 ml), ethyl thiosemicarbazide (1.02 g, 4.4 mmol) and 3 drops of HSO were added, and the reaction mixture was stirred at reflux for 4 h and at ambient temperature for 15 h. The precipitate formed was filtered, washed with EtOH, water, EtO, and dried to give product 5. Yield 1.75 g (74%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 2.58 min). MS (ESI) m / z 583.3 [M−H]. 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 0.99 (s, 9H), 1.11 (t, 3H), 1.20 (t, 3H), 1.41-1.59 (m, 2H), 1.96-2.03 (m, 2H), 2.21-2.29 (m, 1H), 2.71-2.85 (m, 2H),3.53-3.62 (m, 4H), 3.71-3.83 (m, 2H), 7.41-7.48 (m, 6H), 7.61-7.63 (m, 4H). 7.75(t, 1H), 8.57(t, 1H), 10.73(s, 1H), 12.26(s, 1H).

[0449] Synthesis of INT-47, ((2E,2'E)-2,2'-(3-(2-hydroxyethyl)cyclopentane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide)): [ka] To a solution of (2E,2'E)-2,2'-(3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclopentane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide) (0.85 g, 1.46 mmol) in THF (25 ml) was added triethylamine trihydrofluoride at ambient temperature. The resulting mixture was stirred at ambient temperature for 10 h and treated with saturated aqueous ammonium chloride. The solution was extracted with ether and washed with saturated aqueous ammonium chloride and brine. The organic layer was dried over Na2SO4, filtered, and the solvent was concentrated under reduced pressure to give the crude title product. Yield 0.18 g (36%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile with 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.30 min). MS (ESI) m / z 345.0 [M−H]+. 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 1.28 (t, 3H), 1.35 (t, 3H), 1.58-1.81 (m, 2H), 1.86-1.95 (m, 1H), 2.03-2.13 (m, 1H), 2.24-2.33 (m, 1H),2.44-2.57 (m, 1H), 2.65-2.77 (m, 1H),2.85-2.93 (m, 1H), 3.31-3.53 (m, 1H), 3.68-2.82 (m, 5H), 7.25-7.32 (m, 1H), 7.41-7.48 (m, 1H), 8.75 (s, 1H), 12.27 (s, 1H).

[0450] Synthesis of ZN-47: [ka] Zn(OAc)2H2O (0.58 g, 2.7 mmol) was added to INT-47 (0.61 g, 1.8 mmol) in ethanol. The mixture was refluxed for 4 hours. The formed complex precipitated from the mixture as a yellow powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried in vacuo. Yield 0.72 g (99%). 1H-NMR (400MHz, DMSO-d6): δ (ppm) 1.09 (t, 3H), 1.14 (t, 3H), 1.35-1.48 (m, 2H), 2.01-2.11 (m, 2H), 2.51-2.55 (m, 2H), 2.67-2.73 (m, 1H), 2.76-2.84 (m, 1H), 3.47-3.56 (m, 4H), 4.34 (t, 1H), 4.42 (t, 1H), 7.37 (br.s, 1H), 7.85 (t, 1H).

[0451] Synthesis of compound 47: [ka] ZN-47 (0.72 g, 1.7 mmol) was dissolved in DMSO (3.6 mL) and a solution of CuCl2H2O (0.39 g, 1.9 mmol) in water (3.6 mL) was added. The mixture was stirred for 5 minutes, and the precipitate was filtered and washed with a saturated solution of potassium carbonate, water, and Et2O. Yield 0.09 g (13%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 minutes, retention time 1.81 minutes). MS (ESI) m / z 406.5 [M−H]+.

[0452] Scheme 22: Synthesis of compound 48 [ka] Synthesis of 2-(cyclopent-2-en-1-yl)ethan-1-ol: To a stirred suspension of LiAlH4 (4.14 g, 109.0 mmol) in THF (250 ml) cooled to 0 °C was slowly added a solution of cyclopent-2-eneacetic acid (5.5 g, 43.6 mmol, 1.0 equiv) in THF (50 ml). The mixture was heated to reflux for 3 h and then cooled to 0 °C. The reaction was quenched with Na2SO4 (10%) and extracted with Et2O (3 × 100 ml). The combined extracts were dried over Na2SO4, filtered, and evaporated. The product was used in the next step without further purification. Yield 4.4 g (90%). 1 H-NMR (400MHz, CDCl3): δ (ppm) 1.40-1.49 (m, 1H), 1.50-1.51 (m, 1H), 1.58-1.64 (m, 1H), 1.67-1.76 (m, 1H), 2.04-2.13 (m, 1H), 2.42-2.37 (m, 2H), 2.78 (br.s, 1H), 3.69-3.77 (m, 2H), 5.68-5.71 (m, 1H), 5.74-5.77 (m, 1H).

[0453] Synthesis of ((2-(cyclopent-2-en-1-yl)ethoxy)methyl)benzene: [ka] To a stirred solution of 2-(cyclopent-2-en-1-yl)ethan-1-ol (1.0 g, 8.9 mmol) in DMF (12 mL) at 0 °C was added NaH (0.5 g, 13.5 mmol, 60-65% in mineral oil) in one portion. After stirring for 30 min, benzyl chloride (2.03 g, 16.1 mmol) was added to the solution. The reaction was stirred overnight, then quenched with water (15 mL) and extracted three times with EtO. The combined extracts were washed with water, brine, dried over NaSO, filtered, and the solvent was evaporated. The crude product was used without purification. Yield 1.8 g (99%). 1H-NMR (400MHz, DMSO-d6): δ (ppm) 1.33-1.41 (m, 1H), 1.46-1.55 (m, 1H), 1.61-1.69 (m, 1H), 1.93-2.02 (m, 1H), 2.14-2.33 (m, 2H), 2.70 (t, 1H), 3.47 (t, 2H), 4.45 (s, 2H), 5.70 (t, 2H), 7.25-7.32 (m, 3H), 7.34-7.45 (m, 2H).

[0454] Synthesis of 3-(2-(benzyloxy)ethyl)cyclopentane-1,2-diol: [ka] ((2-(cyclopent-2-en-1-yl)ethoxy)methyl)benzene (2.2 g, 11.1 mmol) was dissolved in a mixture of HO-tBuOH (1:3), followed by the addition of N-methylmorpholine N-oxide (1.7 g, 14.4 mmol) and OsO (0.008 g of a 4% aqueous solution, 0.001 equiv.). The reaction mixture was stirred at 60 °C until completion, as monitored by TLC (CHCl-CHOH, 20:1). The solid catalyst was filtered and rinsed with EtOAc, and the filtrate was quenched with an aqueous solution of NaSO (10%). The aqueous layer was extracted with EtOAc, and the combined organic extracts were dried over NaSO, filtered, and the solvent was evaporated. The crude product was purified by flash chromatography (CHCl-MeOH, gradient 1:0 to 95:5) to give the title product. Yield 1.64 g (62%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.20 min). MS (ESI) m / z 237.0 [M−H]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 0.95-1.03 (m, 1H), 1.29-1.59 (m, 2H), 1.66-1.68 (m, 1H), 1.69-1.78 (m, 2H), 1.79-1.88 (m, 1H), 3.41-3.48 (m, 2H), 3.45 (qq, 1H), 3.75-3.91 (m, 1H), 4.09 (dd, 1H), 4.32 (dd, 1H), 4.41-4.48 (m, 2H), 7.25-7.36 (m, 5H).

[0455] Synthesis of 3-(2-(benzyloxy)ethyl)cyclopentane-1,2-dione: [ka] Dimethyl sulfoxide (6.1 g, 78.0 mmol) was added to a stirred solution of oxalyl chloride (4.9 g, 39.0 mmol) in dichloromethane (150 ml) at −78° C. After 15 minutes, a solution of 3-(2-(benzyloxy)ethyl)cyclopentane-1,2-diol (3.1 g, 13.0 mmol) in dichloromethane (20 ml) was added slowly (over a 15 minute period), and the resulting solution was stirred at −78° C. for 1 hour. Triethylamine (11.8 g, 117.0 mmol) was then added, and the mixture was stirred at −78° C. for 15 minutes and then allowed to warm to ambient temperature. The reaction mixture was washed with water, the organic layer was dried over NaSO, filtered, and the solvent was evaporated. Yield 2.6 g (87%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.26 min). MS (ESI) m / z 233.1 [MH]+.

[0456] Synthesis of INT-48, ((2E,2'E)-2,2'-(3-(2-(benzyloxy)ethyl)cyclopentane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide)): [ka] 3-(2-(benzyloxy)ethyl)cyclopentane-1,2-dione (2.6 g, 11.4 mmol) was dissolved in EtOH (35 ml), ethyl thiosemicarbazide (2.86 g, 23.9 mmol) and 3 drops of H2SO4 were added, and the reaction mixture was stirred at reflux for 4 h and at ambient temperature for 15 h. The precipitate formed was filtered, washed with EtOH, water, Et2O, and dried to give the product. Yield 0.40 g (9%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile with 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.86 min). MS (ESI) m / z 435.4 [M−H]+. 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 1.12 (t, 3H), 1.19 (t, 3H), 1.46-1.58 (m, 2H), 2.05-2.15 (m, 1H), 2.22-2.32 (m, 1H), 2.53-2.58 (m, 1H), 2.74-2.82 (m, 2H),3.41-3.63 (m, 6H), 4.47 (d, 2H), 7.26-7.37 (m, 5H), 7.77 (t, 1H), 8.66 (t, 1H), 10.74 (s, 1H), 12.25 (s, 1H).

[0457] Synthesis of INT-49, ((2E,2'E)-2,2'-(3-(2-methoxyethyl)cyclopentane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide)): [ka] INT-49 was made using a procedure similar to that for preparing INT-48. Yield 1.1 g (72%). 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 1.73 (t, 2H), 1.97-2.01 (m, 2H), 2.24-2.27 (m, 1H), 2.36-2.39 (m, 1H), 2.53-2.57 (m, 1H), 2.62-2.67 (m, 1H), 3.12 (d, 3H), 3.38-3.45 (m, 1H).

[0458] Synthesis of compound 48: [ka] Cu(OAc)2H2O (0.26 g, 1.12 mmol) was added to INT-48 5 (0.4 g, 0.92 mmol) in ethanol. The mixture was stirred at ambient temperature for 15 h. The formed complex precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum. Yield 0.1 g (22%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.98 min). MS (ESI) m / z 496.5 [M−H]+.

[0459] Synthesis of compound 49: [ka] The title compound was prepared from INT-49 according to the procedure for preparing compound 48. The product precipitated from the reaction mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum. Yield 0.03 g (35%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 2.33 min). MS (ESI) m / z 420.5 [M−H]+.

[0460] Scheme 23: Synthesis of compound 50 [ka] Synthesis of 2-(cyclopent-2-en-1-yl)-1-morpholinoethan-1-one: [ka] Oxalyl chloride (2.41 g, 1.2 equiv.) was added to a solution of 2-cyclopentene-1-acetic acid (2.0 g, 16 mmol) in dichloromethane (100 ml), one drop of DMF was added, and the mixture was stirred at ambient temperature for 2 hours. The solvent was evaporated under reduced pressure, the residue was dissolved in EtOAc, and to this solution EtN (1.92 g, 1.2 equiv.) and morpholine (1.38 g, 1 equiv.) were added. The reaction was stirred overnight at ambient temperature. The reaction mixture was washed with water, and the organic layer was dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO, CHCl-MeOH, 10:1). Yield 2.1 g (67.8%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.16 min, MS (ESI) m / z 196.4 [M−H]+). 1 H-NMR (400MHz, CDCl3): δ (ppm) 1.41-1.53 ​​(m, 1H), 2.12-2.25 (m, 1H), 2.29-2.46 (m, 4H), 3.09-3.21 (m, 1H), 3.42-3.54 (m, 2H), 3.58-3.76 (m, 6H), 5.70-5.74 (m, 1H), 5.75-5.83 (m, 1H).

[0461] Synthesis of 2-(2,3-dihydroxycyclopentyl)-1-morpholinoethan-1-one: [ka] 2-(Cyclopent-2-en-1-yl)-1-morpholinoethan-1-one (2.1 g, 10.7 mmol) was dissolved in a 1:3 mixture of HO-tBuOH, and to the stirred solution was added N-methylmorpholine-N-oxide (1.64 equiv.) and OsO (0.035 g of a 4% aqueous solution, 0.001 equiv.). The reaction mixture was stirred at 60 °C for 4 h and then at ambient temperature for 15 h. The reaction was quenched with NaSO (10%), extracted with EtOAc, and the organic layer was dried over NaSO, filtered, and evaporated. Yield 1.7 g (68.9%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 0.83 min, MS (ESI) m / z 230.3 [M−H]+).

[0462] Synthesis of 3-(2-morpholino-2-oxoethyl)cyclopentane-1,2-dione: [ka] Dimethyl sulfoxide (1.5 g, 1.4 ml, 4 equiv.) was added to a stirred solution of oxalyl chloride (1.83 g, 1.2 ml, 3 equiv.) in dichloromethane (40 ml) at −78° C. After 5 min, a solution of 2-(2,3-dihydroxycyclopentyl)-1-morpholinoethan-1-one (1.1 g, 4.8 mmol, 1 equiv.) in dichloromethane (80 ml) was added slowly (over a 15 min period), and the resulting solution was stirred at −78° C. for 1 h. Triethylamine (2.9 g, 4 ml, 6 equiv.) was then added, and the mixture was stirred at −78° C. for 15 min and then allowed to warm to ambient temperature. The reaction mixture was washed with water, and the organic layer was dried over NaSO, filtered, and evaporated. Yield 0.89 g (82.3%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 0.88 min, MS (ESI) m / z 225.9 [M−H]+).

[0463] Synthesis of INT-50, ((2Z,2'Z)-2,2'-(3-(2-morpholino-2-oxoethyl)cyclopentane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide)): [ka] 3-(2-Morpholino-2-oxoethyl)cyclopentane-1,2-dione (0.89 g, 4 mmol, 1 equiv.) was dissolved in EtOH (25 ml), ethyl thiosemicarbazide (0.94 g, 2 equiv.) and 3 drops of H2SO4 were added, and the reaction mixture was stirred at reflux for 4 h and at ambient temperature for 15 h. The precipitate formed was filtered, washed with EtOH and water, and crystallized from isopropyl alcohol. Yield 0.6 g (35.5%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.33 min, MS (ESI) m / z 428.5 [M-H]+). 1 H-NMR (400MHz, CDCl3): δ (ppm) 1.14 (t, 3H), 1.20 (t, 3H), 1.46-1.56 (m, 1H), 2.14-2.21 (m, 1H), 2.45-2.55 (m, 2H), 2.74-2.87 (m, 1H), 2.89-2.96 (m, 1H), 3.06-3.13 (m, 1H), 3.46 (br.s, 4H), 3.53-3.65 (m, 8H), 7.78 (br.s, 1H), 8.69 (br.s, 1H), 10.75 (br.s, 1H), 12.18 (s, 1H).

[0464] Synthesis of ZN-50: [ka] Zn(OAc)2H2O (0.15 g, 1.5 equiv.) was added to INT-50 (0.2 g, 0.5 mmol, 1 equiv.) in ethanol. The mixture was refluxed for 4 hours. The formed complex precipitated from the mixture as a yellow powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried in vacuo. Yield 0.1 g (43.5%). 1 H-NMR (400MHz, CDCl3): δ (ppm) 1.1 (t, 3H), 1.15 (t, 3H), 1.37-1.49 (m, 1H), 2.06-2.17 (m, 1H), 2.33-2.47 (m, 2H), 2.77-2.87 (m, 1H), 2.88-2.96 (m, 1H), 3.00-3.09 (m, 1H), 3.40-3.65 (m, 12H), 7.40 (br.s, 1H), 7.95 (br.s, 1H).

[0465] Synthesis of compound 50: [ka] ZN-50 (0.075 g, 0.15 mmol, 1 equiv.) was dissolved in DMSO (1.8 ml) and a solution of CuCl2H2O (0.034 g, 1.1 equiv.) in water (1.8 ml) was added. The mixture was stirred for 5 min, filtered, and the precipitate was washed with a saturated solution of potassium carbonate, water, and Et2O. Yield 0.044 g (58.8%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.85 min). MS (ESI) m / z 489.4 [M−H]+.

[0466] Scheme 24: Synthesis of compound 51: [ka] Synthesis of INT-51, ((2E,2'E)-2,2'-(3-methylcyclopentane-1,2-diylidene)bis(N-methylhydrazine-1-carbothioamide)): [ka] 3-Methyl-1,2-cyclopentanedione (2 g, 17.8 mmol, 1 equiv.) was dissolved in EtOH (100 ml), methyl thiosemicarbazide (3.75 g, 2 equiv.) and 3 drops of H2SO4 were added, and the reaction mixture was stirred at reflux for 4 h and at ambient temperature for 15 h. The precipitate formed was filtered, washed with EtOH, water, Et2O, and dried. Yield: 3.87 g (80%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.34 min, MS (ESI) m / z 287.0 [MH]+). 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 1.05-1.27 (m, 9H), 1.35-1.48 (m, 1H), 2.01-2.15 (m, 1H), 2.47-2.56 (m, 1H), 2.71-2.82 (m, 2H), 3.49-3.63 (m, 4H), 7.74 (br.s, 1H), 8.65 (br.s, 1H), 10.74 (s, 1H), 12.23 (s, 1H).

[0467] Synthesis of INT-52, ((2E,2'E)-2,2'-(3-methylcyclopentane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide)): [ka] INT-52 was made using a procedure similar to that for preparing INT-51. Yield: 5 g (90.5%). LCMS (C18 column 20 x 2 mm, 2.5 μm particle size, 100 A pore size, water-acetonitrile + 0.1% TFA, 5 to 87% gradient in 3 min, retention time 1.59 min, MS (ESI) m / z 315.1 [M-H]+). 1H-NMR (400MHz, DMSO-d6): δ (ppm) 1.16 (d, 3H), 1.36-1.47 (m, 1H), 2.09-2.16 (m, 1H), 2.45-2.65 (m, 1H), 2.69-2.82 (m, 2H), 3.02 (br.s, 6H), 7.88 (br.s, 1H), 8.60 (br.s, 1H), 10.82 (s, 1H), 12.33 (s, 1H).

[0468] Synthesis of INT-53, ((2E,2'E)-2,2'-(3-methylcyclopentane-1,2-diylidene)bis(N-(2-(diethylamino)ethyl)hydrazine-1-carbothioamide)): [ka] INT-53 was made using a procedure similar to that for preparing INT-51. Yield 0.5 g (25%). 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 0.92-0.99 (m, 12H), 1.17 (d, 3H), 1.38-1.47 (m, 1H), 2.10-2.18 (m, 1H), 2.58-2.67 (m, 4H), 2.74-2.82 (m, 2H), 3.54-3.63 (m, 4H), 7.79 (br.s, 1H), 8.50 (br.s, 1H), 10.80 (s, 1H), 12.21 (s, 1H).

[0469] Synthesis of compound 51: [ka] Cu(OAc)2H2O (0.61 g, 1.1 equiv.) was added to thiosemicarbazone 1 (0.73 g, 2.5 mmol, 1 equiv.) in ethanol. The mixture was stirred at ambient temperature for 15 h. The formed complex precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum. Yield 0.46 g (51.9%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 2.51 min). MS (ESI) m / z 348.0 [M−H]+.

[0470] Synthesis of compound 52: [ka] The title compound was prepared from INT-52 according to the procedure for preparing compound 51. The complex precipitated from the reaction mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum. Yield 0.7 g (79%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 2.62 min). MS (ESI) m / z 376.3 [M−H]+.

[0471] Synthesis of compound 53: [ka] The title compound was prepared from INT-53 according to the procedure for preparing compound 51. The product precipitated from the reaction mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum. Yield 0.07 g (15%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.25 min). MS (ESI) m / z 518.3 [M−H]+.

[0472] Example 4: Preparation of compounds 54-65 Synthesis of INT-56, ((2Z,2'E)-2,2'-(1-(pyridin-4-yl)propane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide)): [ka] INT-55 was made using a procedure similar to that for preparing INT-1 in Example 1. Yield 0.030 g (5%). LCMS (C18 column 100 x 4.6 mm, 5.0 μm, 100 Å pore size, water-acetonitrile + 0.1% TFA, 10 min gradient 5 to 87%, retention time 5.01 min). MS (ESI) m / z 352.6 [M−H]+. 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 0.89 (t, 3H), 1.16 (t, 3H), 2.36 (s, 3H), 3.60 (m, 4H), 6.82 (t, 1H), 7.32 (d, 2H), 7.73 (d, 1H), 8.73 (d, 2H), 9.37 (s, 1H), 10.77 (s, 1H).

[0473] Synthesis of INT-58, ((2Z,2'E)-2,2'-(1-(pyridin-2-yl)propane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide)): [ka] INT-58 was made using a procedure similar to that for preparing INT-1 in Example 1. Yield 0.75 g (76.4%). 1H-NMR (400MHz, DMSO D6): δ (ppm) 0.99 (t, 3H), 1.16 (t, 3H), 2.38 (s, 3H), 3.36-3.46 (m, 2H), 3.56-3.66 (m, 2H), 7.36 (t, 1H), 7.55 (dd, 1H), 7.66 (d, 1H), 8.01 (t, 1H), 8.73-8.75 (m, 2H), 10.58 (s, 1H), 11.82 (s, 1H).

[0474] Synthesis of INT-62, ((2Z,2'E)-2,2'-(1-(pyridin-3-yl)propane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide)): [ka] INT-62 was made using a procedure similar to that for preparing INT-1 in Example 1. Yield 0.69 g (65%). LCMS (C18 column 100 x 4.6 mm, 5.0 μm, 100 Å pore size, water-acetonitrile + 0.1% TFA, 10 min gradient 5 to 87%, retention time 4.71 min). MS (ESI) m / z 352.1 [M−H]+. 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 0.90 (t, 3H), 1.15 (t, 3H), 2.37 (s, 3H), 3.60 (m, 4H), 6.81 (t, 1H), 7.53 (m, 1H), 7.71 (d, 1H), 8.43 (s, 1H), 8.65-8.70 (m, 2H), 9.73 (br.s, 1H), 10.65 (br.s, 1H).

[0475] Synthesis of INT-64, ((2E,2'E)-2,2'-(1-(4-(dimethylamino)phenyl)propane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide)): [ka] INT-64 was made using a procedure similar to that for preparing INT-1 in Example 1. Yield 0.67 g (68.4%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.54 min, MS (ESI) m / z 394.5 [M−H]+). 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 0 / 94 (t, 3H), 1.15 (t, 3H), 2.33 (s, 3H), 2.87 (s, 6H), 6.85 (d, 2H), 7.02 (br.s), 7.11 (d, 2H), 8.71 (br.s, 1H), 10.72 (s, 1H).

[0476] Synthesis of compound 56: [ka] The title compound was prepared from INT-56 according to the method for preparing compound 1 in Example 1. The complex was isolated as a reddish-brown powder. After cooling, the product was collected by filtration, washed with water (2 × 15 ml), ethanol (2 × 15 ml), and then dried under vacuum to give the title product. Yield 0.010 g (28%). LCMS (C18 column 20 × 2 mm, 2.5 μm, 100 Å pore size, water-acetonitrile + 0.1% TFA, 5 to 87% gradient in 4 min, retention time 3.41 min). MS (ESI) m / z 413.5 [M−H]+.

[0477] Synthesis of compound 58: [ka] The title compound was prepared from INT-58 according to the method for preparing compound 1 in Example 1. The product precipitated from the reaction mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum. Yield 0.044 g (18.6%). LCMS (C18 column 20 x 2 mm, 2.5 μm, 100 Å pore size, water-acetonitrile + 0.1% TFA, 5 to 87% gradient in 4 min, retention time 1.36 min). MS (ESI) m / z 413.4 [M−H]+.

[0478] Synthesis of compound 62: [ka] The title compound was prepared from INT-62 according to the method for preparing compound 1 in Example 1. The product was isolated as a reddish-brown powder. After cooling, the precipitate formed was collected by filtration, washed with water (2 x 15 ml), ethanol (2 x 15 ml), and then dried under vacuum. Yield 0.094 g (27%). LCMS (C18 column 20 x 2 mm, 2.5 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.72 min). MS (ESI) m / z 413.5 [M−H]+.

[0479] Synthesis of compound 64 [ka] The title compound was prepared from INT-64 according to the method for preparing compound 1 in Example 1. The product precipitated from the reaction mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum. Yield 0.037 g (18%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 2.31 min). MS (ESI) m / z 455.1 [M−H]+.

[0480] Synthesis of INT-63, ((2Z,2'E)-2,2'-(1-(4-(dimethylamino)phenyl)ethane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide)): [ka] INT-63 was made using a procedure similar to that for preparing INT-34 in Example 2. Yield 0.57 g (35%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.63 min, MS (ESI) m / z 380.5 [M-H]+). 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 1.12-1.24 (m, 6H), 2.96 (s, 6H), 3.53-3.67 (m, 4H), 6.75 (d, 2H), 7.64 (d, 2H), 7.88 (br.s, 1H), 8.22 (s, 1H), 8.76 (br.s, 1H), 11.73 (s, 1H), 12.18 (s, 1H).

[0481] Synthesis of compound 63: [ka] The title compound was prepared from INT-63 according to the method for preparing compound 43 in Example 2. The product precipitated from the reaction mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum. Yield 0.075 g (47%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 2.07 min). MS (ESI) m / z 441.1 [M−H]+.

[0482] Synthesis of INT-55, ((2E,2'E)-2,2'-(pentane-2,3-diylidene)bis(N-(tert-butyl)hydrazine-1-carbothioamide)): [ka] INT-55 was made using a procedure similar to that for preparing INT-51 in Example 3. Yield 1.97 g (34%). NMR (400 MHz, DMSO-d6): 0.96 (s, 3H), 1.50 (s, 9H), 1.52 (s, 9H), 2.10 (s, 3H), 2.74 (q, 2H), 7.75 (s, 1H), 7.79 (s, 1H), 10.30-10.48 (m, 2H).

[0483] Synthesis of INT-65, ((2E,2'E)-2,2'-(pentane-2,3-diylidene)bis(N-ethylhydrazine-1-carbothioamide)): [ka] INT-65 was made using a procedure similar to that for preparing INT-51 in Example 3. Yield 2.37 g (49%). 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 0.91 (t, 3H), 1.14 (t, 6H), 2.19 (s, 3H), 2.80 (q, 2H), 3.54 (q, 4H), 8.25-8.40 (m, 2H), 10.15 (s, 1H), 10.27 (s, 1H).

[0484] Synthesis of compound 55: [ka] The title compound was prepared from INT-55 according to the method for preparing compound 51 in Example 3. The product precipitated from the reaction mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum. Yield 0.4 g (82%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 3.41 min). MS (ESI) m / z 420.6 [M−H]+.

[0485] Synthesis of compound 65: [ka] The title compound was prepared from INT-65 according to the method for preparing compound 51 in Example 3. The complex formed precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum. Yield 0.4 g (82%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 2.68 min). MS (ESI) m / z 364.3 [M−H]+.

[0486] Scheme 25: Synthesis of compound 54 [ka] Synthesis of N-(furan-2-ylmethyl)hydrazinecarbothioamide: [ka] To a solution of 2-(isothiocyanatomethyl)tetrahydrofuran (10 g, 71.8 mmol) in EtOH (100 ml) was added hydrazine hydrate (4.5 g, 89.75 mmol) at 0 °C and the reaction mixture was stirred for 3 h. The formed precipitate was collected by filtration, washed with ethanol (2 × 150 ml), and dried to give 1. Yield 9.3 g (76%). 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 1.52-1.60 (m, 1H), 1.76-1.90 (m, 3H), 3.39-3.45 (m, 1H), 3.59-3.66 (m, 2H), 3.76 (q, 1H), 3.93-3.99 (m, 1H), 4.47 (s, 2H), 7.74 (s, 1H), 8.67 (s, 1H).

[0487] Synthesis of INT-54, ((2Z,2'E)-2,2'-(pentane-2,3-diylidene)bis(N-(furan-2-ylmethyl)hydrazine-1-carbothioamide)): [ka] 2,3-Pentanedione (0.4 g, 4 mmol) was dissolved in EtOH (60 mL), N-(furan-2-ylmethyl)hydrazinecarbothioamide (1.37 g, 8 mmol), and 3 drops of H2SO4 were added, and the reaction mixture was stirred at reflux for 4 h and then at room temperature overnight. The reaction progress was monitored by TLC (CHCl3-MeOH 10:1). The precipitate was filtered, washed with EtOH, water, and Et2O, and dried. Yield 0.9 g (55%). LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile with 0.1% TFA, gradient 5 to 87% in 3 min, retention time 1.70 min). MS (ESI) m / z 407.5 [MH]+. 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 0.90 (t, 3H), 2.19 (s, 3H), 2.90 (q, 2H), 4.82 (d, 4H), 6.27-6.29 (m, 2H), 6.40 (s, 2H), 7.58 (s, 2H), 8.65 (t, 1H), 8.73 (t, 1H), 10.42 (s, 1H), 10.53 (s, 1H).

[0488] Synthesis of compound 54: [ka] Cu(OAc)2·2H2O (0.12 g, 1.1 equiv.) was added to INT-54 (0.2 g, 0.5 mmol, 1 equiv.) in ethanol. The mixture was stirred at ambient temperature for 15 h. The formed complex precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, and diethyl ether, and then dried under vacuum. Yield: 0.022 g (9.5%). LCMS (C18 column 20 × 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 2.62 min). MS (ESI) m / z 468.4 [M−H]+.

[0489] Scheme 26: Synthesis of compound 57 [ka] Synthesis of 2-oxo-2-(pyridin-2-yl)acetaldehyde: [ka] To a solution of 1-(pyridin-2-yl)ethan-1-one (10.0 g, 82.5 mmol) in DMSO (150 mL) was added 47% HBr (28 mL, 247.5 mmol), and the mixture was stirred at 60 °C overnight. The reaction was quenched with NaHCO and diluted with water to a total volume of 1000 mL. The product was extracted with EtOAc (3 × 150 mL), and the combined organic layers were dried over anhydrous NaSO, filtered, and the solvent removed under reduced pressure to give the crude product as a yellow oil. Yield 2.8 g (23%). LCMS (C18 column 20 × 2 mm, 2.5 μm, 100 Å pore size, water-acetonitrile with 0.1% TFA, gradient 5 to 87% in 3 min, retention time 0.32 min). MS (ESI) m / z 136.1 [M−H].

[0490] Synthesis of INT-57, ((2Z,2'E)-2,2'-(1-(pyridin-2-yl)ethane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide)): [ka] Ethyl thiosemicarbazide (1.76 g, 14.0 mmol) and one drop of H2SO4 were added to a solution of 2-oxo-2-(pyridin-2-yl)acetaldehyde (1.0 g, 7.0 mmol) in EtOH (50 mL), and the reaction was heated to reflux for 4 h. The precipitate was filtered, washed with EtOH, Et2O, and dried. Yield 0.123 g (5.9%). LCMS (C18 column 20 x 2 mm, 2.5 μm, 100 Å pore size, water-acetonitrile + 0.1% TFA, 5 to 87% gradient in 3 min, retention time 1.41 min). MS (ESI) m / z 338.3 [MH]+. 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 1.21 (dt, 6H), 3.56-3.70 (m, 4H), 7.42 (dd, 1H), 7.86-7.93 (m, 2H), 8.41 (d, 1H), 8.58 (d, 1H), 8.89(s, 1H), 8.79 (s, 1H), 9.20 (t, 1H), 12.01 (s, 1H), 12.80 (s, 1H).

[0491] Synthesis of INT-59, ((2Z,2'E)-2,2'-(1-(pyridin-3-yl)ethane-1,2-diylidene)bis(N-methylhydrazine-1-carbothioamide)): [ka] INT-59 was made using a procedure similar to that for preparing INT-57. Yield 0.53 g (19%). LCMS (C18 column 20 x 2 mm, 2.5 μm, 100 Å pore size, water-acetonitrile + 0.1% TFA, 10 min gradient 5 to 87%, retention time 4.49 min). MS (ESI) m / z 310.4 [M−H]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 3.0 (s, 3H), 3.06 (s, 3H), 7.80 (dd, 1H), 8.2(s, 1H), 8.58(d, 1H), 8.78(d, 1H), 8.89(s, 1H), 8.92-8.98(m, 1H), 9.16(s, 1H), 11.78(s, 1H), 12.09(s, 1H).

[0492] Synthesis of INT-60, ((2Z,2'E)-2,2'-(1-(pyridin-3-yl)ethane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide)): [ka] INT-60 was made using a procedure similar to that for preparing INT-57. Yield 0.90 g (30%). LCMS (C18 column 20 x 2 mm, 2.5 μm, 100 Å pore size, water-acetonitrile + 0.1% TFA, 10 min gradient 5 to 87%, retention time 5.26 min). MS (ESI) m / z 338.5 [M−H]+. 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 1.17 (t, 6H), 3.61 (q, 4H), 7.47 (dd, 1H), 8.0(t, 1H), 8.18(d, 1H), 8.22(s, 1H), 8.62(d, 1H), 8.98-9.07(m, 1H), 11.77(s, 1H), 12.31(s, 1H).

[0493] Synthesis of INT-61, ((2Z,2'E)-2,2'-(1-(pyridin-4-yl)ethane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide)): [ka] INT-61 was made using a procedure similar to that for preparing INT-57. Yield: 180 mg (7%). LCMS (C18 column 20 x 2 mm, 2.5 μm, 100 Å pore size, water-acetonitrile + 0.1% TFA, 10 min gradient 5 to 87%, retention time 4.97 min). MS (ESI) m / z 338.5 [M−H]+. 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 1.18 (t, 3H), 1.20 (t, 3H), 3.58 (q, 2H), 3.64 (q, 2H), 7.80 (d, 1H), 8.04(t, 1H), 8.24(s, 1H), 8.65(d, 1H), 9.12(t, 1H), 11.79(s, 1H), 12.47(s, 1H).

[0494] Synthesis of compound 57: [ka] To a solution of INT-57 (0.123 g, 0.365 mmol) in EtOH (10 ml) was added a solution of CuCl₂·2H₂O (0.062 g, 0.365 mmol) in EtOH (2 ml). The mixture was stirred overnight at room temperature. The precipitate formed was collected by filtration, washed with water (2 × 10 ml), ethanol (2 × 10 ml), diethyl ether (5 × 5 ml), and dried under vacuum. Yield: 0.06 g (41.4%). LCMS (C18 column 20 × 2 mm, 2.5 μm, 100 Å pore size, water-acetonitrile + 0.1% TFA, gradient 5 to 87% in 4 min, retention time 1.39). MS (ESI) m / z 399.0 [M−H]₂.

[0495] Synthesis of compound 59: [ka] The title compound was prepared from INT-59 according to the procedure for preparing compound 57. The title product was collected by filtration, washed with water (2 x 50 ml), ethanol (2 x 50 ml), and diethyl ether (5 x 50 ml), and then dried under vacuum. Yield 230 mg (95%). LCMS (C18 column 20 x 2 mm, 2.5 μm, 100 Å pore size, water-acetonitrile + 0.1% TFA, 5 to 87% gradient in 4 min, retention time 1.34, 1.47 min). MS (ESI) m / z 371.0 [M-H]+.

[0496] Synthesis of compound 60: [ka] The title compound was prepared from INT-60 according to the procedure for preparing compound 57. The title product was collected by filtration, washed with water (2 x 50 ml), ethanol (2 x 50 ml), and diethyl ether (5 x 50 ml), and then dried under vacuum. Yield 218 mg (92%). LCMS (C18 column 20 x 2 mm, 2.5 μm, 100 Å pore size, water-acetonitrile + 0.1% TFA, 5 to 87% gradient in 4 min, retention time 1.58, 1.73 min). MS (ESI) m / z 399.0 [M-H]+.

[0497] Synthesis of compound 61: [ka] The title compound was prepared from INT-61 according to the procedure for preparing compound 57. The product was collected by filtration, washed with water (2 x 50 ml), ethanol (2 x 50 ml), and diethyl ether (5 x 50 ml), and then dried under vacuum. Yield 140 mg (66%). LCMS (C18 column 20 x 2 mm, 2.5 μm, 100 Å pore size, water-acetonitrile + 0.1% TFA, 5 to 87% gradient in 4 min, retention time 1.48, 1.66 min). MS (ESI) m / z 399.0 [M-H]+.

[0498] Example 5: Preparation of Compounds 66-78 Scheme 27: Synthesis of compound 66 [ka] Synthesis of N-methoxy-N-methyl-2-(pyridin-3-yl)acetamide: [ka] To a mixture of 3-pyridineacetic acid (25.0 g, 0.144 mol), Weinreb amine (16.8 g, 0.172 mol), HOBt (23.3 g, 0.172 mol), and triethylamine (71 mL, 0.5 mol) in DCM (400 mL) at 5 °C, EDCI (33.2 g, 172 mol) was added, and the reaction was stirred at ambient temperature for 15 h. The mixture was washed with water (150 mL) and brine (250 mL). The organic layer was dried over anhydrous NaSO, filtered, and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent EtOAc-hexane, 2:1) to give compound 1. Yield: 20.0 g (77%). 1 H-NMR (400 MHz, CDCl3), δ (ppm) : 8.63 - 8.27 (m, 2H), 7.65 (d, J = 7.8 Hz, 1H), 7.28 - 7.03 (m, 1H), 3.76 (s, 2H), 3.67 (s, 3H), 3.19 (s, 3H).

[0499] Synthesis of 1-(pyridin-3-yl)propan-2-one: [ka] A solution of N-methoxy-N-methyl-2-(pyridin-3-yl)acetamide (9.5 g, 52.7 mmol, 1 equiv.) in THF (200 ml) was cooled to 5° C., and methylmagnesium bromide (1.4 M in THF, 46.5 ml, 3 equiv.) was added. The reaction mixture was stirred at 5° C. for 2 h, poured into aqueous NH4Cl, and extracted with Et2O. The combined extracts were dried over anhydrous Na2SO4 and evaporated in vacuo. Compound 2 was used in the next step without further purification. Yield 6.1 g (86%). LC-MS 0.27 min, m / z 136.6 [MH]+.1 H-NMR (400 MHz, CDCl3), δ (ppm) : 8.48 (d, J = 4.7 Hz, 1H), 8.41 (s, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.31 - 7.12 (m, 1H), 3.67 (d, J = 19.5 Hz, 2H), 2.18 (s, 3H).

[0500] Synthesis of INT-66, ((2Z,2'E)-2,2'-(3-(pyridin-3-yl)propane-1,2-diylidene)bis(N-methylhydrazine-1-carbothioamide)): [ka] A mixture of 1-(pyridin-3-yl)propan-2-one (1.3 g, 6.9 mmol, 1 equiv.), NaBr (0.7 g, 1 equiv.), and DMSO (2 ml) was heated to 85 °C and H2SO4 (6 drops) was added (foaming, exothermic). The reaction was heated to 110-115 °C until the formation of dimethyl sulfide ceased and the reaction mixture became viscous. The viscous oil that formed was dissolved in EtOH and methyl thiosemicarbazide (2.023 g, 2 equiv.) was added. The reaction mixture was heated to reflux for 4 h and then stirred at room temperature overnight. The precipitate was collected by filtration, washed with EtOH, MeCN, water, Et2O, and dried to give the title product. Yield 0.95 g (30%). LC-MS 0.97 min, m / z 324.6 [MH]+.

[0501] Synthesis of compound 66: [ka] Copper(II) acetate dihydrate (0.72 g, 1.1 equiv.) was added to a stirred solution of INT-66 (0.12 g, 0.38 mmol, 1 equiv.) in ethanol. The mixture was stirred at room temperature for 15 h. The formed complex precipitated as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, diethyl ether, and dried in vacuo. Yield 0.14 g (99%).

[0502] Scheme 28: Synthesis of compound 67 [ka] Synthesis of N-methoxy-N-methyl-2-(pyridin-4-yl)acetamide: [ka] To a mixture of 4-pyridineacetic acid (4.2 g, 24.2 mmol), Weinreb amine (2.8 g, 29.0 mmol), HOBt (3.9 g, 29.0 mmol), and triethylamine (11.9 mL, 84.7 mmol) in DCM (100 mL) at 5 °C, EDCI (5.6 g, 29.0 mmol) was added, and the reaction was stirred at room temperature for 15 h. The mixture was washed with water (150 mL) and brine (250 mL). The organic layer was dried over anhydrous NaSO, filtered, and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent EtOAc-hexane 2:1) to give the title compound. Yield 2.9 g (66%). LC-MS 0.97 min, m / z 324.6 [MH]. 1 H-NMR (400 MHz, CDCl3), δ (ppm) : 8.55 (d, J = 5.3 Hz, 2H), 7.36 - 7.08 (m, 2H), 3.78 (s, 2H), 3.66 (s, 3H), 3.21 (s, 3H).

[0503] Synthesis of 3-ethoxy-1-(pyridin-4-yl)but-3-en-2-one: [ka] A solution of ethyl vinyl ether (4.1 ml, 41.8 mmol) in anhydrous THF (30 ml) was cooled to -78 °C, and tert-butyllithium (1.7 M in pentane, 23 ml, 38.8 mmol) was added. The mixture was warmed to 0 °C over a 1-hour period, stirred for 45 minutes, and cooled to -30 °C. A solution of N-methoxy-N-methyl-2-(pyridin-4-yl)acetamide (0.7 g, 3.8 mmol) in THF (15 ml) was added, and the reaction was stirred at 0 °C for 4 hours. The progress of the reaction was monitored by TLC. The mixture was poured into aqueous NH Cl (30 ml) and extracted with Et O (3 × 50 ml). The combined extracts were dried over anhydrous Na SO , filtered, and evaporated in vacuo. The product was used in the next step without further purification. Yield 0.2 g (27%). LC-MS 0.66 min, m / z 192.4 [MH]+. 1 H-NMR (400 MHz, CDCl3), δ (ppm) : 8.54 (dd, J = 4.4, 1.6 Hz, 2H), 7.23 - 7.06 (m, 2H), 5.23 (t, J = 11.8 Hz, 1H), 4.42 (t, J = 14.5 Hz, 1H), 3.99 (s, 2H), 3.83 (q, J = 7.0 Hz, 2H), 1.40 (t, J = 7.0 Hz, 3H).

[0504] Synthesis of INT-67, ((2Z,2'E)-2,2'-(1-(pyridin-4-yl)butane-2,3-diylidene)bis(N-methylhydrazine-1-carbothioamide)): [ka] 3-Ethoxy-1-(pyridin-4-yl)but-3-en-2-one (0.2 g, 1.05 mmol, 1 equiv.) was dissolved in EtOH (20 ml), methyl thiosemicarbazide (0.22 g, 2.1 mmol, 2 equiv.) and 3 drops of H2SO4 were added, and the reaction mixture was heated to reflux for 4 h and then stirred at room temperature for 15 h. The formed precipitate was filtered, washed with EtOH, water, Et2O, and dried. Yield 0.21 g (60.2%). LC-MS 0.91 min, m / z 338.9 [MH]+. 1 H-NMR (400 MHz, DMSO), δ (ppm) : 10.85 (s, 1H), 10.35 (s, 1H), 8.78 (d, J = 6.6 Hz, 2H), 8.51 (d, J = 4.6 Hz, 1H), 8.34 (d, J = 4.5 Hz, 1H), 7.72 (d, J = 6.5 Hz, 2H), 4.76 (s, 2H), 3.00 (dd, J = 14.4, 4.6 Hz, 6H), 2.28 (s, 3H).

[0505] Synthesis of compound 67: [ka] Copper(II) acetate dihydrate (0.09 g, 0.46 mmol) was added to a stirred solution of thiosemicarbazone 3 (0.15 g, 0.44 mmol) in ethanol. The mixture was stirred at room temperature for 15 h. The formed complex precipitated as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, diethyl ether, and dried in vacuo. Yield 0.075 g (42.3%).

[0506] Scheme 29: Synthesis of compound 68 [ka] Synthesis of ethyl 2-(pyridin-3-yl)acetate: [ka] To a stirred solution of 3-pyridineacetic acid (25.0 g, 145 mmol) in EtOH (250 mL) at 0-5 °C, SOCl (11.6 mL, 160 mmol) was added in small portions over 15 min intervals. After the addition was complete, the reaction was heated to reflux for an additional 16 h, and the EtOH was evaporated under reduced pressure. To the residue was added 2 M aqueous NaCO (30 mL), and the resulting mixture was extracted with EtOAc (3 × 400 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give compound 1 as a colorless liquid. Yield 22.3 g (93%). 1 H-NMR (400MHz, CDCl3), δ (ppm) : 1.26 (t, 3 H), 3.62 (s, 2 H), 4.17 (q, 2 H), 7.27-7.28 (m, 1 H), 7.64-7.65 (m, 1 H), 8.53 (m, 2 H).

[0507] Synthesis of ethyl 1-(pyridin-3-yl)cyclopentane-1-carboxylate: [ka] To a stirred suspension of sodium hydride (7.3 g, 181 mmol, 60% in mineral oil) in anhydrous THF (160 ml) at 0 °C, a solution of ethyl 2-(pyridin-3-yl)acetate (10.0 g, 60.5 mmol) in anhydrous THF (35 ml) was added dropwise. The reaction mixture was stirred at 0 °C until effervescence no longer occurred. 1,4-Dibromobutane (19.6 g, 90.5 mmol) was then added at 0 °C, and the reaction mixture was stirred at room temperature for 14 h. The reaction mixture was then quenched with saturated aqueous ammonium chloride solution (60 ml). The reaction mixture was extracted with EtOAc (3 × 40 ml). The organic phase was washed with brine (100 ml), dried over anhydrous NaSO, filtered, and concentrated to dryness in vacuo. The crude material (19 g) was obtained as a dark solid, which was then purified by flash chromatography (silica gel, eluent hexane / ethyl acetate 4:1 to 1:1). Yield 9.8 g (74%). LC-MS 1.01 min, m / z 220.6 [MH]+. 1H-NMR (400MHz, CDCl3), δ (ppm) : 1.16 (t, 3H), 1.74-1.78 (m, 4H), 1.88-1.98 (m, 2H), 2.67-2.73 (m, 2H), 4.09 (q, 2H), 7.23-7.27 (m, 1H), 7.67-7.71 (m, 1H), 8.49 (dd, 1H), 8.65 (dd, 1H).

[0508] Synthesis of 1-(pyridin-3-yl)cyclopentane-1-carboxylic acid: [ka] A solution of ethyl 1-(pyridin-3-yl)cyclopentane-1-carboxylate (8.4 g, 38.5 mmol) in MeOH (60 ml) was added to a solution of LiOH (2.5 g, 96.2 mmol) in water (10 ml). The reaction mixture was stirred at 60 °C for 8 h. The solvent was then removed by lyophilization, and the corresponding crude product was used in the next step without further purification. Yield 7 g (80%). LC-MS 0.82 min, m / z 192.1 [M−H]+. 1 H-NMR (400MHz, DMSO-d6), δ (ppm) : 1.66-1.70 (m, 4H), 1.85-1.92 (m, 2H), 2.52-2.58 (m, 2H), 7.56 (dd, 1H), 7.98-8.02 (m, 1H), 8.58 (dd, 1H), 8.66 (d, 1H), 12.66 (br.s, 1H).

[0509] Synthesis of N-methoxy-N-methyl-1-(pyridin-3-yl)cyclopentane-1-carboxamide: [ka] To a mixture of 1-(pyridin-3-yl)cyclopentane-1-carboxylic acid (5.0 g, 22.0 mmol), Weinreb amine (2.6 g, 26.4 mmol), HOBt (3.6 g, 26.4 mmol), and triethylamine (10.8 mL, 77 mmol) in DCM (150 mL) at 4 °C, EDCI (5.1 g, 26.4 mmol) was added, and the reaction was stirred at room temperature overnight. The mixture was then washed with water (100 mL) and brine (100 mL). The organic layer was dried over anhydrous NaSO and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: DCM 100% to DCM / MeOH 95:5 (v / v)) to give the crude product. Yield: 2.5 g (49%). LC-MS: 0.84 min, m / z 235.3 [M−H]. 1 H-NMR (400 MHz, CDCl3), δ (ppm) : 1.66-1.81 (m, 4H), 2.05-2.11 (m, 2H), 2.42-2.48 (m, 2H), 2.89 (s, 3H), 3.13 (s, 3H), 7.34 (q, 1H), 7.65 (d, 1H), 8.49 (d, 1H), 8.59 (d, 1H).

[0510] Synthesis of 1-(1-(pyridin-3-yl)cyclopentyl)ethan-1-one: [ka] A solution of N-methoxy-N-methyl-1-(pyridin-3-yl)cyclopentane-1-carboxamide (1.27 g, 5.42 mmol, 1 equiv.) in THF (100 ml) was cooled to 5° C., and methylmagnesium bromide (1.4 M in THF, 39.1 ml, 10 equiv.) was added. The reaction mixture was stirred at 5° C. for 2 h, poured into aqueous NH4Cl, and extracted with Et2O. The combined extracts were dried over anhydrous Na2SO4 and evaporated in vacuo. The title product was used in the next step without further purification. Yield 1 g (97%). LC-MS 1.14 min, m / z 190.6 [MH]+.

[0511] Synthesis of INT-68, ((2Z,2'E)-2,2'-(1-(1-(pyridin-3-yl)cyclopentyl)ethane-1,2-diylidene)bis(N-methylhydrazine-1-carbothioamide)) [ka] Compound 6. A mixture of 1-(1-(pyridin-3-yl)cyclopentyl)ethan-1-one (1.3 g, 6.9 mmol, 1 equiv.), NaBr (0.7 g, 1 equiv.), and DMSO (2 ml) was heated to 85 °C and H2SO4 (6 drops) was added (foaming, exothermic). The reaction was heated at 110-115 °C until the formation of dimethyl sulfide ceased and the reaction mixture became viscous. The viscous oil that formed was dissolved in EtOH and methyl thiosemicarbazide (1.44 g, 2 equiv.) was added. The reaction mixture was heated to reflux for 4 h and then stirred at room temperature overnight. The precipitate was collected by filtration, washed with EtOH, MeCN, water, Et2O, and dried to give the title product. Yield 0.5 g (19%). LC-MS 1.10 min, m / z 378.8 [MH]+. 1 H-NMR (400 MHz, DMSO), δ (ppm) : 12.05 (s, 1H), 11.51 (s, 1H), 8.57 (s, 2H), 8.44 (d, J = 3.9 Hz, 1H), 7.76 (dd, J = 24.5, 5.8 Hz, 2H), 7.59 (s, 1H), 7.36 (dd, J = 7.7, 4.8 Hz, 1H), 3.02 (dd, J = 46.9, 4.3 Hz, 6H), 2.50 (s, 1H), 2.46 (s, 2H), 2.00 (d, J = 12.5 Hz, 2H), 1.64 (s, 4H).

[0512] Synthesis of compound 68 [ka] Copper(II) chloride dihydrate (0.078 g, 0.46 mmol) was added to a stirred solution of INT-68 (0.16 g, 0.42 mmol) in ethanol (30 ml). The mixture was stirred at room temperature for 15 hours. The complex was isolated as a reddish-brown powder. The precipitate that formed was filtered, washed with water (2 x 50 ml), ethanol (2 x 50 ml), and copious amounts of diethyl ether (5 x 50 ml), and then dried under vacuum. Yield 0.04 g (22%).

[0513] Scheme 30: Synthesis of compound 69 [ka] Synthesis of ethyl 2-(pyridin-3-yl)acetate: [ka] To a stirred solution of 3-pyridineacetic acid (25.0 g, 145 mmol) in EtOH (250 ml) at 0-5 °C, SOCl (11.6 ml, 160 mmol) was added over a 15-minute interval. After the addition was complete, the reaction was heated to reflux for an additional 16 hours, and then the EtOH was evaporated under reduced pressure. To the residue was added 2 M aqueous NaCO (30 ml), and the resulting mixture was extracted with EtOAc (3 x 400 ml). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the title product as a colorless liquid. Yield 22.3 g (93%). 1 H-NMR (400MHz, CDCl3), δ (ppm) : 1.26 (t, 3 H), 3.62 (s, 2 H), 4.17 (q, 2 H), 7.27-7.28 (m, 1 H), 7.64-7.65 (m, 1 H), 8.53 (m, 2 H).

[0514] Synthesis of ethyl 2-(pyridin-3-yl)butanoate: [ka] To a solution of ethyl 2-(pyridin-3-yl)acetate (10.08 g, 61 mmol) in THF (100 mL) was added sodium hydride (2.54 g, 66 mmol, 60% dispersion in oil) in small portions. After stirring at room temperature for 10 min, iodoethane (5.1 mL, 66 mmol) was added, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then quenched with aqueous NH4Cl, extracted with EtOAc, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give compound 2 as a colorless liquid. Yield 10.6 g (86%). LC-MS 0.77 min, m / z 194.1 [MH]+. 1 H-NMR (400MHz, CDCl3), δ (ppm) : 0.91 (t, J=8Hz, 3H), 1.22 (t, J=8Hz, 3H), 1.74-1.85 (m, 1H), 2.07-2.18 (m, 1H), 3.46 (t, J=7.6Hz, 1H), 4.07-4.21 (m, 2H), 7.25-7.28 (m, 1H), 7.67-7.70 (m, 1H), 8.51-8.54 (m, 2H).

[0515] Synthesis of 2-(pyridin-3-yl)butanoic acid: [ka] A solution of ethyl 2-(pyridin-3-yl)butanoate (10.6 g, 54.8 mmol) in MeOH (60 ml) was added to a solution of NaOH (5.5 g, 137.2 mmol) in water (22 ml). The reaction mixture was stirred at room temperature for 8 hours. The solvent was then removed by lyophilization, and the corresponding crude product was used in the next step without further purification. Yield 10.3 g (93%). LC-MS 0.51 min, m / z 166.1 [M−H]+. 1H-NMR (400MHz, CDCl3), δ (ppm) : 0.81 (t, J=6.8Hz, 3H), 1.67-1.78 (m, 1H), 1.96-2.05 (m, 1H), 2.08 (s, 1H), 3.60 (t, J=7.6Hz, 1H), 7.53-7.56 (m, 1H), 7.92-7.95 (m, 1H), 8.56-8.61 (m, 2H).

[0516] Synthesis of N-methoxy-N-methyl-2-(pyridin-3-yl)butanamide: [ka] To a mixture of 2-(pyridin-3-yl)butanoic acid (10.3 g, 51.0 mmol), Weinreb amine (5.9 g, 61.2 mmol), HOBt (8.3 g, 61.2 mmol), and triethylamine (25 mL, 176 mmol) in DCM (150 mL) at 4 °C, EDCI (11.7 g, 61.2 mmol) was added, and the reaction was stirred at room temperature overnight. The mixture was washed with water (100 mL) and brine (100 mL). The organic layer was dried over anhydrous NaSO and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent DCM 100% to DCM / MeOH 95:5 (v / v)) to give the crude product. Yield 7.3 g (68%). LC-MS 0.76 min, m / z 208.9 [M−H]+. 1 H-NMR (400MHz, CDCl3), δ (ppm) : 0.90 (t, J=7.6Hz, 3H), 1.73-1.80 (m, 1H), 2.08-2.15 (m, 1H), 3.17 (s, 3H), 3.57 (s, 3H), 3.91-3.96 (m, 1H), 7.26-7.28 (m, 1H), 7.74-7.77 (m, 1H), 8.48-8.50 (m, 1H), 8.53 (d, J=2Hz, 1H).

[0517] Synthesis of 2-ethoxy-4-(pyridin-3-yl)hex-1-en-3-one: [ka] A solution of ethyl vinyl ether (4.3 ml, 45.1 mmol) in anhydrous tetrahydrofuran (30 ml) was cooled to -78 °C, and tert-butyllithium (1.7 M in pentane, 24 ml, 41 mmol) was added. The mixture was warmed to 0 °C over a 1-hour period, stirred for 45 minutes, and cooled to -30 °C. A solution of N-methoxy-N-methyl-2-(pyridin-3-yl)butanamide (1.7 g, 8.2 mmol) in THF (35 ml) was added, and the reaction was stirred at 0 °C for 4 hours. The progress of the reaction was monitored by TLC. The mixture was poured into aqueous NH Cl (30 ml) and extracted with Et O (3 × 50 ml). The combined extracts were dried over anhydrous Na SO , filtered, and evaporated in vacuo. The product was used in the next step without further purification. Yield 1.15 g (64%). LC-MS 1.15 min, m / z 219.9 [MH]+. 1 H-NMR (400 MHz, CDCl3), δ (ppm) : 0.86 (t, J=7.2Hz, 3H), 1.34 (t, J=6.8Hz, 3H), 1.68-1.79 (m, 1H), 2.04-2.15 (m, 1H), 3.62-3.70 (m, 1H), 3.74-3.82 (m, 1H), 4.27 (t, J=8Hz, 1H), 4.35 (d, J=2Hz, 1H), 5.20(d, J=2.8Hz, 1H), 7.23-7.27 (m, 1H), 7.55-7.58 (m, 1H), 8.47-8.49 (m, 1H), 8.52 (d, J=2Hz, 1H).

[0518] Synthesis of INT-69, ((2Z,2'E)-2,2'-(3-(pyridin-3-yl)pentane-1,2-diylidene)bis(N-methylhydrazine-1-carbothioamide)): [ka] Compound 6. To a stirred solution of 2-ethoxy-4-(pyridin-3-yl)hex-1-en-3-one (0.89 g, 4.05 mmol, 1 equiv.) in EtOH (20 ml), methyl thiosemicarbazide (0.85 g, 8.1 mmol, 2 equiv.) and 3 drops of H2SO4 were added, and the reaction mixture was heated to reflux for 4 h and then stirred at room temperature for 15 h. The precipitate that formed was filtered, washed with EtOH, water, Et2O, and dried. Yield 0.67 g (45%). LC-MS 1.01 min, m / z 366.3 [MH]+.

[0519] Synthesis of compound 69 [ka] Copper(II) chloride dihydrate (0.12 g, 0.73 mmol) was added to a stirred solution of INT-69 (0.24 g, 0.67 mmol) in ethanol (30 ml). The mixture was stirred overnight at room temperature. The complex was isolated as a reddish-brown powder. The precipitate that formed was filtered, washed with water (2 x 50 ml), ethanol (2 x 50 ml), and copious amounts of diethyl ether (5 x 50 ml), and then dried under vacuum. Yield 0.13 g (45%).

[0520] Scheme 31: Synthesis of compound 70 [ka] Synthesis of 2-oxo-2-(pyridin-4-yl)acetaldehyde: [ka] To a solution of 1-pyridin-4-ylethanone (10.0 g, 82.5 mmol) in DMSO (100 ml), concentrated HBr (28 ml, 247.5 mmol) was added, and the mixture was stirred at 50 °C overnight. The reaction mixture was quenched with NaHCO and then diluted with water to a total volume of 1000 ml. The resulting solution was extracted with EtOAc (3 × 150 ml), and the combined organic layers were dried over anhydrous NaSO and evaporated in vacuo to give product 1 as a yellow oil. Yield 2.0 g (18%). LC-MS 0.35 min, m / z 136.1 [MH].

[0521] Synthesis of INT-70, ((2Z,2'E)-2,2'-(1-(pyridin-4-yl)ethane-1,2-diylidene)bis(N-methylhydrazine-1-carbothioamide)): [ka] To a solution of 2-oxo-2-(pyridin-4-yl)acetaldehyde (1.2 g, 8.9 mmol) in EtOH (100 ml) was added methyl thiosemicarbazide (1.87 g, 19.8 mmol), followed by two drops of H2SO4. The reaction mixture was then heated to reflux for 4 hours and stirred at room temperature overnight. The precipitate was filtered, washed with EtOH, Et2O, and dried to give compound 2. Yield 70 mg (4%). LC-MS (reverse-phase C18 column 20 x 2 mm, 2.5 μm, 100 Å pore size, water-acetonitrile + 0.1% TFA, gradient 5 to 87% over 10 min), 4.27 min, (ESI) m / z 310.1 [MH]+.

[0522] Synthesis of compound 70 [ka] To a solution of INT-70 (70 mg, 0.2 mmol) in EtOH (10 ml) was added a solution of copper(II) chloride dihydrate (42 mg, 0.22 mmol) in EtOH (2 ml). The mixture was stirred at room temperature overnight. The formed precipitate was collected by filtration, washed with water (2 × 5 ml), ethanol (2 × 5 ml), diethyl ether (5 × 5 ml), and then dried under vacuum to give the product as a dehydrated powder. Yield 42 mg (50%).

[0523] Scheme 32: Synthesis of compound 71 [ka] Synthesis of 1-(pyridin-3-yl)propan-2-one: [ka] A solution of N-methoxy-N-methyl-2-(pyridin-3-yl)acetamide (9.5 g, 52.7 mmol, 1 equiv.) in THF (200 ml) was cooled to 5° C., and methylmagnesium bromide (1.4 M in THF, 46.5 ml, 3 equiv.) was added. The reaction mixture was stirred at 5° C. for 2 h, poured into aqueous NH4Cl, and extracted with Et2O. The combined extracts were dried over anhydrous Na2SO4 and evaporated in vacuo. The title product was used in the next step without further purification. Yield 6.1 g (86%). LC-MS 0.27 min, m / z 136.6 [MH]+. 1 H-NMR (400 MHz, CDCl3), δ (ppm) : 8.48 (d, J = 4.7 Hz, 1H), 8.41 (s, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.31 - 7.12 (m, 1H), 3.67 (d, J = 19.5 Hz, 2H), 2.18 (s, 3H).

[0524] Synthesis of INT-71, ((2Z,2'E)-2,2'-(3-(pyridin-3-yl)propane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide)): [ka] A mixture of 1-(pyridin-3-yl)propan-2-one (1.5 g, 11.1 mmol, 1 equiv.), NaBr (1.14 g, 1 equiv.), and DMSO (2 ml) was heated to 85 °C and H2SO4 (6 drops) was added (foaming, exothermic). The reaction was heated to 110-115 °C until the formation of dimethyl sulfide ceased and the reaction mixture became viscous. The viscous oil that formed was dissolved in EtOH and ethyl thiosemicarbazide (2.64 g, 2 equiv.) was added. The reaction mixture was heated to reflux for 4 h and then stirred at room temperature overnight. The precipitate was collected by filtration, washed with EtOH, MeCN, water, Et2O, and dried to give the title product. Yield 0.175 g (4.5%). LC-MS 1.19 min, m / z 352.8 [M−H]+.

[0525] Synthesis of compound 71: [ka] Copper acetate(II) dihydrate (0.055 g, 1 equiv.) was added to a stirred solution of INT-71 (0.175 g, 0.5 mmol, 1 equiv.) in ethanol. The mixture was stirred at room temperature for 15 h. The formed complex precipitated as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, diethyl ether, and dried in vacuo. Yield 0.14 g (69%).

[0526] Scheme 33: Synthesis of compound 72 [ka] Synthesis of 3-((3r,5r,7r)-adamantan-1-yl)-N-methoxy-N-methylpropanamide: [ka] To a stirred mixture of 3-((3r,5r,7r)-adamantan-1-yl)propanoic acid (5 g, 24 mmol), N,O-dimethylhydroxylamine (2.81 g, 1.2 equiv.), HOBt (3.89 g, 1.2 equiv.), and triethylamine (8.5 ml, 6.11 g, 2.5 equiv.) in DCM (50 ml) at 5 °C, EDCI (5.52 g, 1.2 equiv.) was added, and the reaction was stirred at room temperature for 15 h. The mixture was washed with water and brine. The organic layer was dried over anhydrous NaSO and then concentrated under reduced pressure. The product was purified by column chromatography (silica gel, eluent CCl 100%, then CCl / EtOAc 8:2). Yield 3.5 g (58%). LC-MS 1.88 min, m / z 252.4 [M−H]. 1 H-NMR (400 MHz, CDCl3), δ (ppm) : 3.71 (d, J = 1.6 Hz, 3H), 3.19 (s, 3H), 2.42 - 2.31 (m, 2H), 1.97 (s, 3H), 1.72 (d, J = 11.9 Hz, 3H), 1.68 - 1.58 (m, 4H), 1.50 (s, 6H), 1.43 (dd, J = 9.8, 7.1 Hz, 2H).

[0527] Synthesis of 5-((3r,5r,7r)-adamantan-1-yl)-2-ethoxypent-1-en-3-one: [ka] A solution of ethyl vinyl ether (2.01 g, 2.7 ml, 3.3 equiv.) in anhydrous THF (150 ml) was cooled to −78° C., and tert-butyllithium (1.7 M in pentane, 16 ml, 3 equiv.) was added. The mixture was warmed to 0° C. over a 1-hour period, stirred for 45 minutes, and then cooled to −30° C. A solution of 3-((3r,5r,7r)-adamantan-1-yl)-N-methoxy-N-methylpropanamide (2.12 g, 8.4 mmol) in THF (15 ml) was added, and stirring was continued at 0° C. for 4 hours. The mixture was poured into aqueous NH4Cl (100 ml) and extracted with Et2O (3 × 100 ml). The combined extracts were dried over anhydrous Na2SO4, filtered, and the solvent was evaporated in vacuo. The product was used in the next step without further purification. Yield 2.2 g (99.9%). 1 H-NMR (400 MHz, CDCl3), δ (ppm) : 5.18 (s, 1H), 4.36 (d, J = 33.6 Hz, 1H), 3.82 (q, J = 6.9 Hz, 2H), 2.64 (dd, J = 20.9, 13.1 Hz, 2H), 1.97 (s, 4H), 1.79 - 1.53 (m, 8H), 1.56 - 1.15 (m, 13H).

[0528] Synthesis of INT-72, ((2E,2'E)-2,2'-(5-((3r,5r,7r)-adamantan-1-yl)pentane-2,3-diylidene)bis(N-ethylhydrazine-1-carbothioamide): [ka] 5-((3r,5r,7r)-Adamantan-1-yl)-2-ethoxypent-1-en-3-one (2.21 g, 8.4 mmol) was dissolved in EtOH (60 ml), and ethyl thiosemicarbazide (2.01 g, 2 equiv.) and 3 drops of H2SO4 were added. The stirred reaction mixture was heated to reflux for 4 h and then maintained at room temperature for 15 h. The formed precipitate was filtered, washed with EtOH, saturated aqueous Na2CO3, water, Et2O, and dried. Yield 2.2 g (59.6%). LC-MS 2.17 min, m / z 437.5 [MH]+.

[0529] Synthesis of compound 72 [ka] Copper(II) chloride dihydrate (0.23 g, 1 equiv.) was added to a stirred solution of INT-72 (0.59 g) in ethanol. The mixture was stirred at room temperature for 15 hours. The complex formed precipitated as a reddish-brown powder. The precipitate was collected by filtration, washed with water, diethyl ether, and dried. Yield 0.61 g (90.8%).

[0530] Scheme 34: Synthesis of compound 73 [ka] Synthesis of 3-cyclopentyl-N-methoxy-N-methylpropanamide: [ka] To a stirred mixture of 3-cyclopentylpropanoic acid (3.12 g, 21.9 mmol), N,O-dimethylhydroxylamine (2.57 g, 1.2 equiv.), HOBt (4.03 g, 1.2 equiv.), and triethylamine (6.1 mL, 4.43 g, 2 equiv.) in DCM (100 mL) at 5 °C, EDCI (5.05 g, 1.2 equiv.) was added, and the reaction was stirred at room temperature for 15 h. The mixture was washed with water and brine. The organic layer was dried over anhydrous NaSO and then concentrated under reduced pressure. The product was purified by column chromatography (silica gel, eluent DCM 100% to DCM / MeOH 99:1). Yield 3.11 g (76.5%). LC-MS 1.63 min, m / z 186.4 [M−H]+. 1H-NMR (400 MHz, CDCl3), δ (ppm) : 3.69 (s, 3H), 3.19 (s, 3H), 2.42 (dd, J = 18.1, 10.2 Hz, 2H), 2.53 - 2.33 (m, 2H), 1.87 - 1.73 (m, 4H), 1.70 - 1.57 (m, 5H), 1.58 - 1.44 (m, 2H), 1.19 - 1.01 (m, 2H).

[0531] Synthesis of 5-cyclopentyl-2-ethoxypent-1-en-3-one: [ka] A solution of ethyl vinyl ether (3.85 g, 5.1 ml, 6.6 equiv.) in anhydrous THF (100 ml) was cooled to -78 °C, and tert-butyllithium (1.7 M in pentane, 28 ml, 6 equiv.) was added. The mixture was warmed to 0 °C over a 1-hour period, stirred for 45 minutes, and then cooled to -30 °C. A solution of 3-cyclopentyl-N-methoxy-N-methylpropanamide (1.5 g, 8 mmol) in THF (15 ml) was added, and stirring was continued at 0 °C for 4 hours. The mixture was poured into aqueous NH Cl (100 ml) and extracted with Et O (3 × 100 ml). The combined extracts were dried over anhydrous Na SO , filtered, and the solvent was evaporated in vacuo. The product was used in the next step without further purification. Yield 1.05 g (99.0%). LC-MS 0.91 min, m / z 180.9 [MH].

[0532] Synthesis of INT-73, ((2E,2'E)-2,2'-(5-cyclopentylpentane-2,3-diylidene)bis(N-ethylhydrazine-1-carbothioamide)): [ka] 5-Cyclopentyl-2-ethoxypent-1-en-3-one (1.05 g, 8 mmol) was dissolved in EtOH (25 ml), and ethyl thiosemicarbazide (1.93 g, 2 eq.) and 3 drops of H2SO4 were added. The stirred reaction mixture was heated to reflux for 4 h and then maintained at room temperature for 15 h. The precipitate formed was filtered, washed with EtOH, saturated aqueous Na2CO3, water, Et2O, and dried. Yield 2 g (68%). LC-MS 1.83 min, m / z 371.5 [MH]+.

[0533] Synthesis of compound 73: [ka] Copper(II) chloride dihydrate (0.23 g, 1 equiv.) was added to a stirred solution of INT-73 (0.5 g, 1.3 mmol) in ethanol. The mixture was stirred at room temperature for 15 hours. The formed complex precipitated as a reddish-brown powder. The precipitate was collected by filtration, washed with water, diethyl ether, and dried. Yield 0.5 g (88.7%).

[0534] Scheme 35: Synthesis of compound 74 [ka] Synthesis of INT-74, ((2Z,2'Z)-2,2'-(3-methoxypropane-1,2-diylidene)bis(N-ethylhydrazine-1-carbothioamide)): [ka] A three-neck flask was charged with SeO2 (3.6 g, 1.05 equiv.), 1,4-dioxane (70 mL), and water (14 mL). The mixture was heated to 50 °C and stirred until most of the SeO2 dissolved. 1-Methoxypropan-2-one (2.72 g, 30.9 mmol) was added, and the reaction was heated at gentle reflux overnight. Solid selenium precipitated during the course of the reaction. The mixture was cooled in an ice bath and filtered through diatomaceous earth to remove the selenium. The filter cake was washed with portions of 1,4-dioxane. The filtrate was evaporated to dryness and dissolved in EtOH (100 mL). Ethyl thiosemicarbazide (7.35 g, 2 equiv.) and 3 drops of H2SO4 were added. The stirred reaction mixture was heated to reflux for 4 h. The precipitate that formed was filtered, washed with EtOH, saturated aqueous Na2CO3, water, Et2O, and dried. Yield 2.4 g (25.5%). LC-MS 1.37 min, m / z 305.5 [M−H]+.

[0535] Synthesis of compound 74: [ka] Copper(II) chloride dihydrate (0.1 g, 1 equiv.) was added to a stirred solution of INT-74 (0.184 g, 0.6 mmol) in ethanol. The mixture was stirred at room temperature for 15 hours. The complex formed precipitated as a reddish-brown powder. The precipitate was collected by filtration, washed with water, diethyl ether, and dried. Yield 0.1 g (45.2%).

[0536] Scheme 36: Synthesis of compound 75 [ka] Synthesis of INT-75, ((2Z,2'E)-2,2'-(1-(benzo[d][1,3]dioxol-5-yl)ethane-1,2-diylidene)bis(N-methylhydrazine-1-carbothioamide)): [ka] A three-neck flask was charged with SeO2 (2.12 g, 1.05 equiv.), 1,4-dioxane (41 mL), and water (9 mL). The mixture was heated to 50 °C and stirred until most of the SeO2 was dissolved. 1-(Benzo[d][1,3]dioxol-5-yl)ethan-1-one (2.72 g, 30.9 mmol) was added, and the reaction was heated at gentle reflux overnight. Selenium solids precipitated during the course of the reaction. The mixture was cooled in an ice bath and filtered through diatomaceous earth to remove the selenium. The filter cake was washed with portions of 1,4-dioxane. The filtrate was evaporated to dryness and dissolved in EtOH (100 mL). Methyl thiosemicarbazide (3.84 g, 2 equiv.) and 3 drops of H2SO4 were added. The stirred reaction mixture was heated to reflux for 4 h. The precipitate that formed was filtered, washed with EtOH, saturated aqueous Na2CO3, water, Et2O, and dried. Yield 2.16 g (33.5%). LC-MS 1.53 min, m / z 353.3 [MH]+. 1 H-NMR (400 MHz, DMSO-d6), δ (ppm) : 12.13 (s, 1H), 11.71 (s, 1H), 8.82 (d, J = 4.3 Hz, 1H), 8.21 - 8.04 (m, 2H), 7.60 (d, J = 1.5 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.08 (s, 2H), 3.04 (dd, J = 15.0, 4.5 Hz, 6H).

[0537] Synthesis of ZN-75: [ka] Zinc acetate (0.28 g, 1.5 eq) was added to INT-75 (0.36 g, 1 mmol) in ethanol. The mixture was heated to reflux for 4 hours. The formed complex precipitated as a yellow powder. The precipitate was collected by filtration, washed with water, methanol, diethyl ether, and dried in vacuo. Yield 0.33 g (76.8%).

[0538] Synthesis of compound 75: [ka] ZN-75 (0.32 g, 0.8 mmol) was dissolved in DMSO (9 ml) and Cu(OAc)2 in water (9 ml) was added. * A solution of H2O (0.17 g, 1.1 equiv.) was added. The mixture was stirred for 5 min, filtered, and the precipitate was washed with a saturated solution of potassium carbonate, water, and Et2O. Yield 0.15 g (48.5%).

[0539] Scheme 37: Synthesis of compound 76: [ka] Synthesis of 2-(3,5-dimethyl-1H-pyrazol-1-yl)-N-methoxy-N-methylacetamide: [ka] To a stirred mixture of 2-(3,5-dimethyl-1H-pyrazol-1-yl)acetic acid (1.95 g, 12.6 mmol), N,O-dimethylhydroxylamine (1.48 g, 1.2 equiv.), HOBt (2.32 g, 1.2 equiv.), and triethylamine (3.5 ml, 2.54 g, 2 equiv.) in DCM (80 ml) at 5 °C, EDCI (2.9 g, 1.2 equiv.) was added, and the reaction was stirred at room temperature for 15 h. The mixture was washed with water and brine. The organic layer was dried over anhydrous NaSO and then concentrated under reduced pressure. The product was used further without further purification. Yield 1.7 g (68.1%). LC-MS 0.88 min, m / z 198.3 [M−H]. 1 H-NMR (400 MHz, CDCl3), δ (ppm) : 5.88 (s, 1H), 4.98 (s, 2H), 3.79 (s, 3H), 3.22 (s, 3H), 2.23 (d, J = 6.6 Hz, 6H).

[0540] Synthesis of 1-(3,5-dimethyl-1H-pyrazol-1-yl)-3-ethoxybut-3-en-2-one: [ka] A solution of ethyl vinyl ether (6.83 g, 9 ml, 11 equiv.) in anhydrous THF (150 ml) was cooled to −78° C., and tert-butyllithium (1.7 M in pentane, 50 ml, 10 equiv.) was added. The mixture was warmed to 0° C. over a 1-hour period, stirred for 45 minutes, and then cooled to −30° C. A solution of 2-(3,5-dimethyl-1H-pyrazol-1-yl)-N-methoxy-N-methylacetamide (1.7 g, 8.6 mmol) in THF (20 ml) was added, and stirring was continued at 0° C. for 4 hours. The mixture was poured into aqueous NH4Cl (100 ml) and extracted with Et2O (3 × 100 ml). The combined extracts were dried over anhydrous Na2SO4, filtered, and the solvent was evaporated in vacuo. The product was used in the next step without further purification. Yield 0.4 g (22.2%). LC-MS 1.15 min, m / z 209.1 [MH]+.

[0541] Synthesis of INT-76, ((2E,2'E)-2,2'-(1-(3,5-dimethyl-1H-pyrazol-1-yl)butane-2,3-diylidene)bis(N-ethylhydrazine-1-carbothioamide)): [ka] 1-(3,5-Dimethyl-1H-pyrazol-1-yl)-3-ethoxybut-3-en-2-one (0.4 g, 1.9 mmol) was dissolved in EtOH (15 ml), and ethyl thiosemicarbazide (0.46 g, 2 eq.) and 1 drop of H2SO4 were added. The stirred reaction mixture was heated to reflux for 4 h and then maintained at room temperature for 15 h. The formed precipitate was filtered, washed with EtOH, saturated aqueous Na2CO3, water, Et2O, and dried. Yield 0.05 g (6.8%). LC-MS 1.62 min, m / z 383.5 [MH]+.

[0542] Synthesis of compound 76: [ka] Copper(II) chloride dihydrate (0.23 g, 1 equiv.) was added to a stirred solution of INT-76 (0.5 g, 1.3 mmol) in ethanol. The mixture was stirred at room temperature for 15 hours. The formed complex precipitated as a reddish-brown powder. The precipitate was collected by filtration, washed with water, diethyl ether, and dried. Yield 0.5 g (88.7%).

[0543] Scheme 38: Synthesis of compound 77: [ka] Synthesis of INT 77, ((2Z,2'Z)-2,2'-(1-(7-methoxybenzofuran-2-yl)ethane-1,2-diylidene)bis(N-methylhydrazine-1-carbothioamide)): [ka] A three-neck flask was charged with SeO2 (1.84 g, 1.05 equiv.), 1,4-dioxane (36 mL), and water (8 mL). The mixture was heated to 50 °C and stirred until most of the SeO2 was dissolved. 1-(7-Methoxybenzofuran-2-yl)ethan-1-one (3 g, 15.8 mmol) was added, and the reaction was heated at gentle reflux overnight. Selenium solids precipitated during the course of the reaction. The mixture was cooled in an ice bath and filtered through diatomaceous earth to remove the selenium. The filter cake was washed with portions of 1,4-dioxane. The filtrate was evaporated to dryness and dissolved in EtOH (100 mL). Methyl thiosemicarbazide (3.32 g, 2 equiv.) and 3 drops of H2SO4 were added. The stirred reaction mixture was heated to reflux for 4 h. The precipitate that formed was filtered, washed with EtOH, saturated aqueous Na2CO3, water, Et2O, and dried. Yield 2.15 g (36%). LC-MS 1.63 min, m / z 379.3 [MH]+.

[0544] Synthesis of compound 77: [ka] Copper(II) chloride dihydrate (0.15 g, 1 equiv.) was added to a stirred solution of INT-77 (0.34 g, 0.89 mmol) in ethanol. The mixture was stirred at room temperature for 15 hours. The formed complex precipitated as a reddish-brown powder. The precipitate was collected by filtration, washed with water, diethyl ether, and dried. Yield 0.34 g (86.8%).

[0545] Scheme 39: Synthesis of compound 78 [ka] Synthesis of 4-(benzo[d]thiazol-2-yl)-N-methoxybutanamide: [ka] To a stirred mixture of 4-(benzo[d]thiazol-2-yl)butanoic acid (1.22 g, 5.5 mmol), N,O-dimethylhydroxylamine (0.65 g, 1.2 equiv.), HOBt (0.89 g, 1.2 equiv.), and triethylamine (2 mL, 1.44 g, 2.5 equiv.) in DCM (50 mL) at 5 °C, EDCI (1.27 g, 1.2 equiv.) was added and the reaction was stirred at room temperature for 15 h. The mixture was washed with water and brine. The organic layer was dried over anhydrous NaSO and then concentrated under reduced pressure. The product was used further without further purification. Yield 1.46 g (99.9%). LC-MS 1.3 min, m / z 265.1 [MH]+. 1 H-NMR (400 MHz, CDCl3), δ (ppm) : 7.92 (dd, J = 46.1, 8.1 Hz, 2H), 7.41 (dt, J = 15.2, 7.3 Hz, 2H), 3.66 (s, 3H), 3.33 - 3.11 (m, 5H), 2.60 (t, J = 7.1 Hz, 2H), 2.25 (p, J = 7.3 Hz, 2H).

[0546] Synthesis of 6-(benzo[d]thiazol-2-yl)-2-ethoxyhex-1-en-3-one: [ka] A solution of ethyl vinyl ether (1.2 g, 1.6 ml, 5.5 equiv.) in anhydrous THF (40 ml) was cooled to -78 °C, and tert-butyllithium (1.7 M in pentane, 9.4 ml, 5 equiv.) was added. The mixture was warmed to 0 °C over a 1-hour period, stirred for 45 minutes, and then cooled to -30 °C. A solution of 4-(benzo[d]thiazol-2-yl)-N-methoxybutanamide (0.8 g, 3 mmol) in THF (5 ml) was added, and stirring was continued at 0 °C for 4 hours. The mixture was poured into aqueous NH Cl (15 ml) and extracted with Et O (3 × 25 ml). The combined extracts were dried over anhydrous Na SO , filtered, and the solvent was evaporated in vacuo. The product was used in the next step without further purification. Yield 0.83 g (99.6%). LC-MS 1.62 min, m / z 276.3 [MH].

[0547] Synthesis of INT-78, ((2E,2'E)-2,2'-(6-(benzo[d]thiazol-2-yl)hexane-2,3-diylidene)bis(N-methylhydrazine-1-carbothioamide)): [ka] 6-(Benzo[d]thiazol-2-yl)-2-ethoxyhex-1-en-3-one (0.86 g, 3.1 mmol) was dissolved in EtOH (30 ml), and methyl thiosemicarbazide (0.66 g, 2 eq.) and 1 drop of H2SO4 were added. The stirred reaction mixture was heated to reflux for 4 h and then maintained at room temperature for 15 h. The formed precipitate was filtered, washed with EtOH, saturated aqueous Na2CO3, water, Et2O, and dried. Yield 0.79 g (60.1%). LC-MS 1.57 min, m / z 422.3 [MH]+. 1H-NMR (400 MHz, DMSO-d6), δ (ppm) : 10.61 (s, 1H), 10.24 (s, 1H), 8.40 (d, J = 4.4 Hz, 1H), 8.23 ​​(d, J = 4.5 Hz, 1H), 8.07 (dd, J = 25.5, 8.0 Hz, 2H), 7.44 (dt, J = 33.7, 7.7 Hz, 2H), 3.21 (t, J = 7.2 Hz, 2H), 3.14 - 2.92 (m, 8H), 2.21 (s, 3H), 1.89 (d, J = 7.3 Hz, 2H).

[0548] Synthesis of compound 78: [ka] Copper(II) chloride dihydrate (0.32 g, 1 equiv.) was added to a stirred solution of INT-78 (0.79 g, 1.3 mmol) in ethanol. The mixture was stirred at room temperature for 15 hours. The formed complex precipitated as a reddish-brown powder. The precipitate was collected by filtration, washed with water, diethyl ether, and dried. Yield 0.66 g (73.2%).

[0549] Example 6: Preparation of Compounds 79-127 Scheme 40: Synthesis of Compound 79 [ka] Synthesis of ethyl 5-(piperidin-1-ylmethyl)furan-2-carboxylate: [ka] To a solution of ethyl 5-(chloromethyl)furan-2-carboxylate (5 g, 27 mmol) in CH3CN (150 ml) was added piperidine (2.56 g, 1 eq.), potassium carbonate (7.33 g, 2 eq.), and potassium iodide (1.3 g, 0.3 eq.). The reaction mixture was stirred at room temperature overnight. The solid was filtered and the filtrate was concen...

Claims

1. Compound of formula (V): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein: R １ is a 5- to 10-membered heteroaryl, NH ２ , NH(C １ ~C ６ alkyl), or N(C １ ~C ６ alkyl) ２ C optionally substituted with １ ~C ６ is alkyl, R ２ is a 5- to 10-membered heteroaryl, NH ２ , NH(C １ ~C ６ alkyl), or N(C １ ~C ６ alkyl) ２ C optionally substituted with １ ~C ６ is alkyl, R ３ is a 4- to 8-membered heterocycle or a 5-membered heteroaryl, wherein the 4- to 8-membered heterocycle optionally contains a group R ３ａ and the 5-membered heteroaryl is optionally substituted with a group R ３ｂ is substituted once, twice, or three times with R ３ａ But for each occurrence, C １ ~C ６ Alkyl, C １ ~C ６ Alkyl-(C ６ ~C １０ aryl), C １ ~C ６ alkyl-(5- to 10-membered heteroaryl), S(O) ２ H, S (O) ２ -(C １ ~C ６ alkyl), S(O) ２ -(C ３ ~C ７ cycloalkyl), or S(O) ２ -(C ６ ~C １０ aryl), wherein each heteroaryl is optionally selected from C １ ~C ６ Alkyl or C ６ ~C １０ Further substituted 1 to 4 times with aryl, each C ６ ~C １０ Aryl is optionally C １ ~C ６ further substituted 1 to 4 times with alkyl; R ３ｂ But for each occurrence, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkyl-N(R ５ ) ２ , (C １ ~C ６ alkyl)-O-(C １ ~C ６ alkyl), halo, nitro, cyano, C ６ ~C １０ Aryl, C(O)-(4- to 8-membered heterocycle), C １ ~C ６ Alkyl-(C ６ ~C １０ aryl), C １ ~C ６ alkyl-(5- to 10-membered heteroaryl), or C １ ~C ６ alkyl-(4- to 8-membered heterocycle), where each 4- to 8-membered heterocycle, C ６ ~C １０ Aryl and 5- to 10-membered heteroaryl are optionally selected from C １ ~C ３ Alkyl, C １ ~C ３ Alkoxy, C １ ~C ３ further substituted 1 to 4 times with haloalkyl or halo; R ４ is hydrogen or C １－３ is alkyl, R ５ independently for each occurrence: hydrogen, C １ ~C ６ Alkyl, or C １ ~C ３ Alkyl-(C ６ ~C １０ aryl), The compound or a pharmaceutically acceptable salt thereof.

2. R １ is methyl or ethyl, R ２ is methyl or ethyl; The compound of claim 1.

3. R ３ is tetrahydrofuranyl, morpholinyl, piperidinyl, furyl, thiophenyl, pyrrolyl, oxazolyl, pyrazolyl, or imidazolyl, wherein said tetrahydrofuranyl, morpholinyl, and piperidinyl are optionally substituted by a group R ３ａ and wherein said furyl, thiophenyl, pyrrolyl, oxazolyl, pyrazolyl, and imidazolyl are optionally substituted with a group R ３ｂ 3. The compound of claim 1 or claim 2, which is substituted once, twice or three times with

4. R ３ is a group R ３ｂ 4. The compound of any one of claims 1 to 3, wherein the compound is furyl, thiophenyl, oxazolyl, pyrazolyl, or imidazolyl, optionally substituted once, twice, or three times with

5. R ３ｂ But for each occurrence, C １ ~C ６ Alkyl, C １ ~C ６ Alkyl-N(R ５ ) ２ , Haro, C ６ ~C １０ Aryl, C １ ~C ６ alkyl-(4- to 8-membered heterocycle), or C １ ~C ６ Alkyl-(C ６ ~C １０ aryl), wherein each 4- to 8-membered heterocycle and C ６ ~C １０ Aryl is optionally C １ ~C ３ Alkyl, C １ ~C ３ Alkoxy, C １ ~C ３ The compound of any one of claims 1 to 4, further substituted 1 to 4 times with haloalkyl or halo.

6. R ３ｂ but, 【Chemistry 2】 The compound according to any one of claims 1 to 4, selected from the group consisting of:

7. R ３ But C １ ~C ３ Alkyl-N(C １ ~C ４ alkyl) ２ or C １ ~C ３ furyl optionally substituted once with alkyl-(5- to 6-membered heterocycle), wherein said 5- to 6-membered heterocycle is optionally selected from the group consisting of C １ ~C ３ The compound of any one of claims 1 to 4, further substituted 1 to 4 times with alkyl.

8. R ３ but, 【Transformation 3】 The compound according to any one of claims 1 to 3, selected from the group consisting of:

9. R ４ The compound according to any one of claims 1 to 8, wherein is hydrogen or methyl. 【Request Item 10】 【Chemistry 4-1】 【Chemistry 4-2】 【Chemistry 4-3】 【Chemistry 4-4】 [Chemistry 4-5] [Chemistry 4-6] 【Chemistry 4-7】 【Chemistry 4-8】 10. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

11. Compound of formula (IV): 【Transformation 5】 or a pharmaceutically acceptable salt thereof, wherein: L is C ３ ~C ７ Cycloalkyl, C １ ~C ６ alkyl or absent, R １ is a 5- to 10-membered heteroaryl, NH ２ , NH(C １ ~C ６ alkyl), or N(C １ ~C ６ alkyl) ２ C optionally substituted with １ ~C ６ is alkyl, R ２ is a 5- to 10-membered heteroaryl, NH ２ , NH(C １ ~C ６ alkyl), or N(C １ ~C ６ alkyl) ２ C optionally substituted with １ ~C ６ is alkyl, R ３ But C ６ ~C １０ Aryl, 5- to 10-membered heteroaryl, C ３ ~C １０ cycloalkyl, or C(O)NH—(C １ ~C ６ alkyl)-PPh3, wherein the C ６ ~C １０ The aryl is a group R ３ａ and the 5- to 10-membered heteroaryl is optionally substituted with a group R ３ｂ is substituted once, twice, or three times with R ３ａ But for each occurrence, C ３ ~C ７ cycloalkyl or a 4- to 8-membered heterocycle, wherein said 4- to 8-membered heterocycle is optionally selected from the group consisting of C １ ~C ３ further substituted once, twice, or three times with alkyl; R ３ｂ But for each occurrence, C １ ~C ３ Alkyl, C １ ~C ３ Alkoxy, C ３ ~C ７ cycloalkyl, or a 4- to 8-membered heterocycle, wherein the heterocycle is optionally selected from the group consisting of C １ ~C ３ further substituted once, twice, or three times with alkyl; R ４ But hydrogen, C １ ~C ３ Alkyl, or C ６ ~C １０ Although it is aryl, However, if L is absent, R ３ is a group R ３ａ C substituted once, twice, or three times with ６ ~C １０ aryl, or when L is absent, R ３ is a group R ３ｂ provided that the heteroaryl is a 6- to 10-membered heteroaryl substituted once, twice, or three times with The compound or a pharmaceutically acceptable salt thereof. 【Request Item 12】 【Chemistry 6-1】 【Chemistry 6-2】 【Transformation 6-3】 【Chemistry 6-4】 12. The compound of claim 11, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

13. Compounds of formula (III): 【Transformation 7】 or a pharmaceutically acceptable salt thereof, wherein: L is C １ ~C ６ alkyl or absent, R １ is a 5- to 10-membered heteroaryl, NH ２ , NH(C １ ~C ６ alkyl), or N(C １ ~C ６ alkyl) ２ C optionally substituted with １ ~C ６ is alkyl, R ２ is a 5- to 10-membered heteroaryl, NH ２ , NH(C １ ~C ６ alkyl), or N(C １ ~C ６ alkyl) ２ C optionally substituted with １ ~C ６ is alkyl, R ３ But C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkyl, halo, hydroxy, C(O)NH ２ , C(O)NH(C １ ~C ６ alkyl), C(O)N(C １ ~C ６ alkyl) ２ or C(O)-(4- to 8-membered heterocycle), wherein １ ~C ６ Alkyl and the C １ ~C ６ The alkoxy is optionally selected from C ６ ~C １０ aryl), and the C(O)-(4- to 8-membered heterocycle) is optionally substituted with C １ ~C ３ substituted once, twice, or three times with alkyl; The compound or a pharmaceutically acceptable salt thereof. 【Request Item 14】 【Chemistry 8】 14. The compound of claim 13, selected from the group consisting of: or a pharmaceutically acceptable salt thereof. 【Request Item 15】 【Chemistry 9】 1. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof. 【Request Item 16】 【Chemistry 10】 or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier.

18. 18. The pharmaceutical composition of claim 17 for use in the treatment of a neurodegenerative disease.

19. 19. The pharmaceutical composition of claim 18, wherein the neurodegenerative disease is amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Parkinson's disease, Huntington's disease, and Alzheimer's disease.

20. 20. The pharmaceutical composition of claim 18 or 19, wherein the neurodegenerative disease is ALS.

21. 21. The pharmaceutical composition of claim 20, wherein the ALS is familial or sporadic.

22. The pharmaceutical composition according to any one of claims 18 to 21, wherein the subject in need thereof is treatment-naive.

23. 22. The pharmaceutical composition of claim 20 or claim 21, wherein the subject in need thereof has received previous treatment for ALS.

24. 24. The pharmaceutical composition of any one of claims 20 to 23, wherein the subject in need thereof is a human, and the human has a genetic mutation associated with ALS.

25. 25. The pharmaceutical composition of claim 24, wherein the genetic mutation associated with ALS comprises a mutation in the SOD1 gene.

26. 26. The pharmaceutical composition of any one of claims 20 to 25, wherein the compound is administered to a subject in combination with an additional ALS treatment therapy.

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